1-Phenyl-3-azabicyclo[3.1.0]hexanes

ABSTRACT

Substituted 3-azabicyclo[3.1.0]hexanes, acid addition salts, method of use and method of preparation are described. The compounds have anxiolytic and analgesic activity.

This is a division of application Ser. No. 809,339 filed June 23, 1978,now U.S. Pat. No. 4,131,611 which is a continuation-in-part of ourcopending application Ser. No. 723,402, filed Sept. 15, 1975, and nowabandoned which is in turn a continuation-in-part of our copendingapplication Ser. No. 601,128, filed July 31, 1975, and now abandoned.

BACKGROUND OF THE INVENTION

Applicants are not aware of any prior art references which, in theirrespective judgment as one skilled in the anxiolytic and analgesic art,would anticipate or render obvious the novel compounds of the instantinvention; however, for the purpose of fully developing the backgroundof the invention and establishing the state of the requisite art, thefollowing references are set forth: U.S. Pat. No. 3,166,571, U.S. Pat.No. 3,065,230, and Synthesis of Pyrrolidines By IntramolecularCarbonionic Epoxide Opening, R. Achini and W. Oppolzer, TetrahedronLetters No. 6, 369-72 (1975).

SUMMARY OF THE INVENTION

The first embodiment of the instant invention is represented byoptically active compounds of the formula: ##STR1## wherein the phenylmoiety is unsubstituted or mono- or di-substituted from the groupconsisting of halogen, straight chain C₁ -C₆ alkyl, C₁ -C₆ alkoxy,trifluoromethyl, nitro, amino, acetamido and hydroxy; X is selected fromthe group consisting of hydrogen, straight chain C₁ -C₈ alkyl, and amoiety of the formula C_(n) H_(2n) R₁, wherein n is an integer from 1 to3 and R₁ is selected from the group consisting of phenyl andp-fluorobenzoyl; the racemic mixture thereof; the mirror image thereof;and the non-toxic pharmaceutically acceptable salts thereof.

A preferred embodiment of the first embodiment consists of thosecompounds wherein the phenyl moiety is di-substituted from the groupconsisting of halogen, straight chain C₁ -C₆ alkyl, C₁ -C₆ alkoxy,trifluoromethyl, nitro, amino, acetamido and hydroxy; and X is aspreviously defined.

A second preferred embodiment of the first embodiment consists of thosecompounds wherein the phenyl moiety is unsubstituted or mono-substitutedfrom the group consisting of halogen, straight chain C₁ -C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl, nitro, amino, acetamido and hydroxy; and Xis as previously defined.

A most preferred embodiment of the second preferred embodiment consistsof those compounds wherein X is selected from the group consisting ofhydrogen and straight chain C₁ -C₈ alkyl.

A further preferred embodiment of the most preferred embodiment consistsof those compounds wherein the phenyl moiety is para or meta substitutedfrom the group consisting of straight chain C₁ -C₆ alkyl, halogen andtrifluoromethyl; and X is as previously defined.

A still further preferred embodiment of the further preferred embodimentconsists of those compounds wherein the phenyl moiety is para or metasubstituted from the group consisting of methyl, ethyl, chloro, fluoro,bromo and trifluoromethyl; and X is as previously defined.

A most preferred embodiment of the still further preferred embodimentconsists of those compounds wherein the phenyl moiety is substituted aspreviously defined; and X is selected from the group consisting ofhydrogen and methyl.

The second embodiment of the instant invention is represented byoptically active compounds of the formula: ##STR2## wherein the phenylmoiety is mono- or di-substituted from the group consisting of phenyl,halophenyl, C₁ -C₆ alkoxy methyl and C₃ -C₆ cycloalkyl; X is selectedfrom the group consisting of hydrogen, straight chain C₁ -C₈ alkyl, anda moiety of the formula C_(n) H_(2n) R₁, wherein n is an integer from 1to 3 and R₁ is selected from the group consisting of halophenyl,bis-halophenyl and aminophenyl; the racemic mixture thereof; the mirrorimage thereof; and the non-toxic pharmaceutically acceptable saltsthereof.

A preferred embodiment of the second embodiment consists of thosecompounds wherein the phenyl moiety is di-substituted from the groupconsisting of phenyl, halophenyl, C₁ -C₆ alkoxy methyl and C₃ -C₆cycloalkyl; and X is as previously defined.

A second preferred embodiment of the second embodiment consists of thosecompounds wherein the phenyl moiety is mono-substituted from the groupconsisting of phenyl, halophenyl, C₁ -C₆ alkoxy methyl and C₃ -C₆cycloalkyl; and X is as previously defined.

A most preferred embodiment of the second preferred embodiment consistsof those compounds wherein X is selected from the group consisting ofhydrogen and straight chain C₁ -C₈ alkyl.

A further preferred embodiment of the most preferred embodiment consistsof those compounds wherein the phenyl moiety is para or meta substitutedfrom the group consisting of phenyl, halophenyl, and C₁ -C₆alkoxymethyl; and X is as previously defined.

A still further preferred embodiment of the further preferred embodimentconsists of those compounds wherein the phenyl moiety is para or metasubstituted from the group consisting of phenyl, mono-chlorophenyl,di-chlorophenyl, methoxymethyl and ethoxymethyl; and X is as previouslydefined.

A most preferred embodiment of the still further preferred embodimentconsists of those compounds wherein the phenyl moiety is substituted aspreviously defined; and X is selected from the group consisting ofhydrogen and methyl.

The third embodiment of the instant invention is represented byoptically active compounds of the formula: ##STR3## wherein the phenylmoiety is mono- or di-substituted from the group consisting of halogen,straight chain C₁ -C₆ alkyl, C₁ -C₆ alkoxy, trifluoromethyl, nitro,amino, acetamido and hydroxy; X is selected from the group consisting ofC₃ -C₆ cycloalkylmethyl, C₃ -C₆ alkenyl and C₃ -C₆ alkynyl; the racemicmixture thereof; the mirror image thereof; and the non-toxicpharmaceutically acceptable salts thereof.

A preferred embodiment of the third embodiment consists of thosecompounds wherein the phenyl moiety is di-substituted from the groupconsisting of halogen, straight chain C₁ -C₆ alkyl, C₁ -C₆ alkoxy,trifluoromethyl, nitro, amino, acetamido and hydroxy; and X is aspreviously defined.

A second preferred embodiment of the third embodiment consists of thosecompounds wherein the phenyl moiety is unsubstituted or mono-substitutedfrom the group consisting of halogen, straight chain C₁ -C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl, nitro, amino, acetamido and hydroxy and Xis as previously defined.

A most preferred embodiment of the second preferred embodiment consistsof those compounds wherein X is selected from the group consisting ofcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, allyl, butenyl,dimethylallyl and propargyl.

A further preferred embodiment of the most preferred embodiment consistsof those compounds wherein the phenyl moiety is para or meta substitutedfrom the group consisting of straight chain C₁ -C₆ alkyl, halogen andtrifluoromethyl; and X is as previously defined.

A still further preferred embodiment of the further preferred embodimentconsists of those compounds wherein the phenyl moiety is para or metasubstituted from the group consisting of methyl, ethyl, chloro, fluoro,bromo and trifluoromethyl; and X is as previously defined.

A most preferred embodiment of the further preferred embodiment consistsof those compounds wherein the phenyl moiety is substituted aspreviously defined; and X is selected from the group consisting ofcyclopropylmethyl, allyl and propargyl.

The fourth embodiment of the instant invention is represented byoptically active compounds of the formula: ##STR4## wherein the phenylmoiety is unsubstituted or mono- or di-substituted from the groupconsisting of halogen, straight chain C₁ -C₆ alkyl, C₁ -C₆ alkoxy,trifluoromethyl, nitro, amino, acetamido and hydroxy; X is selected fromthe group consisting of hydrogen, straight chain C₁ -C₈ alkyl, C₃ -C₆cycloalkylmethyl, C₃ -C₆ alkenyl, C₃ -C₆ alkynyl, and a moiety of theformula C_(n) H_(2n) R₁, wherein n is an integer from 1 to 3 and R₁ isselected from the group consisting of phenyl and p-fluorobenzoyl; R isselected from the group consisting of hydrogen and C₁ -C₃ alkyl; withthe proviso that at least one R must be selected from the groupconsisting of C₁ -C₃ alkyl; the racemic mixture thereof; the mirrorimage thereof; and the non-toxic pharmaceutically acceptable saltsthereof.

A preferred embodiment of the fourth embodiment consists of thosecompounds wherein the phenyl moiety is di-substituted from the groupconsisting of halogen, straight chain C₁ -C₆ alkyl, C₁ -C₆ alkoxy,trifluoromethyl, nitro, amino, acetamido and hydroxy; and R and X are aspreviously defined.

A second preferred embodiment of the fourth embodiment consists of thosecompounds wherein the phenyl moiety is unsubstituted or mono-substitutedfrom the group consisting of halogen, straight chain C₁ -C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl, nitro, amino, acetamido and hydroxy; and Rand X are as previously defined.

A most preferred embodiment of the second preferred embodiment consistsof those compounds wherein X is selected from the group consisting ofhydrogen and straight chain C₁ -C₈ alkyl; and R is as previouslydefined.

A further preferred embodiment of the most preferred embodiment consistsof those compounds wherein the phenyl moiety is para or meta substitutedfrom the group consisting of straight chain C₁ -C₆ alkyl, halogen andtrifluoromethyl; and R and X are as previously defined.

A still further preferred embodiment of the further preferred embodimentconsists of those compounds wherein the phenyl moiety is para or metasubstituted from the group consisting of methyl, ethyl, chloro, fluoro,bromo and trifluoromethyl; X is as previously defined; and R ismono-substituted at the carbon 2- or carbon 4-position.

A most preferred embodiment of the still further preferred embodimentconsists of those compounds wherein the phenyl moiety is substituted aspreviously defined; X is selected from the group consisting of hydrogenand methyl; and R is as previously defined.

The fifth embodiment of the instant invention is represented byoptically active compounds of the formula: ##STR5## wherein the phenylmoiety is mono-substituted from the group consisting of C₁ -C₆ alkyl;and X is selected from the group consisting of hydrogen and C₁ -C₈alkyl.

A preferred embodiment of the fifth embodiment consists of thosecompounds wherein the phenyl moiety is mono-substituted from the groupconsisting of C₁ -C₃ alkyl; and X is selected from the group consistingof hydrogen and C₁ -C₃ alkyl.

A most preferred embodiment of the preferred embodiment consists ofthose compounds wherein the phenyl moiety is mono-substituted at thepara-position with a compound selected from the group consisting ofmethyl and ethyl; and X is selected from the group consisting ofhydrogen and methyl.

The sixth embodiment of the instant invention is represented byoptically active compounds of the formula: ##STR6## wherein the phenylmoiety is mono-substituted from the group consisting of C₁ -C₆ alkyl;and R₁ is selected from the group consisting of hydrogen and C₁ -C₆alkyl.

A preferred embodiment of the sixth embodiment consists of thosecompounds wherein the phenyl moiety is mono-substituted from the groupconsisting of C₁ -C₃ alkyl; and X is selected from the group consistingof hydrogen and C₁ -C₃ alkyl.

A most preferred embodiment of the preferred embodiment consists ofthose compounds wherein the phenyl moiety is mono-substituted at thepara-position with a compound selected from the group consisting ofmethyl and ethyl; and X is selected from the group consisting of methyland ethyl; and X is selected from the group consisting of hydrogen andmethyl.

The seventh embodiment of the instant invention is represented byoptically active compounds of the formula: ##STR7## wherein the phenylmoiety is mono-substituted from the group consisting of halogen,straight chain C₁ -C₆ alkyl, C₁ -C₆ alkoxy, trifluoromethyl, nitro,amino, acetamido and hydroxy; and W is selected from the groupconsisting of electronegative leaving moieties.

A preferred embodiment of the seventh embodiment consists of thosecompounds wherein the phenyl moiety is mono-substituted as previouslydefined; and W is selected from the group consisting of methanesulfonyl,toluenesulfonyl, chloride, iodine and bromine.

A most preferred embodiment of the preferred embodiment consists ofthose compounds wherein the phenyl moiety is mono-substituted at thepara-position from the group consisting of methyl, ethyl, chloro,fluoro, bromo and trifluoromethyl; and X is methanesulfonyl.

The salts can be, for example, hydrochloride, hydrobromide, hydriodide,sulfate, nitrate, phosphate, maleate, succinate and the like.

DESCRIPTION OF THE INVENTION

The compounds of the present invention may be prepared by the followingreaction sequence: ##STR8## wherein R and X are as defined above; thecompounds of Formula I are dissolved in a solvent such as benzene,toluene, ether, tetrahydrofuran, and, the like and reacted with areducing agent such as sodium bis(2-methoxyethoxy)aluminum hydride at atemperature from about 0° to 125° C., preferably from 25° C. to about80° C., for a period of one to four hours. The reaction mixture iscooled and a strong base such as potassium hydroxide is added. Theorganic layer is concentrated and the product is collected byfiltration.

The starting material shown as compounds (I) above may be prepared asfollows: ##STR9## wherein R and X are as defined above.

The reaction ingredients are heated in an aprotic solvent, such asxylene, for 6-24 hours and the product is recovered by evaporation ofthe solvent.

In producing the compounds of formula (II) a wide variety of otherhydride reducing agents, such as, diborane or lithium aluminum hydridemay be used. In this instance the compounds of formula (I) are suspendedin tetrahydrofuran, the reducting agent is added and the reaction iscarried out at 0°-80° C. for 1 to 4 hours. The reaction mixture iscooled, acidified with an acid such as hydrochloric, the aqueous layeris separated and the product is liberated by the addition of a strongbase such as potassium hydroxide.

Alternatively, the compounds of this invention of formula II above maybe prepared by the reaction of lactams of either of the followingformulae: ##STR10## wherein R and X are as defined above, with asuitable reducing agent, such as lithium aluminum hydride, diborane,sodium bis(2-methoxyethoxy)aluminum hydride in an aprotic solvent suchas ether, benzene, or tetrahydrofuran at a temperature of 0°-80° C. fora period of one to six hours. The compound of formula II is isolated asdescribed above for the reduction of the corresponding imides of formulaI.

The above reduction may be carried out with a limited quantity of theabove mentioned reducing agents so that when R is as defined above and Xis hydrogen the intermediates of the following formulae may also beobtained: ##STR11## X is not hydrogen, intermediates of the followingformulae may be obtained: These compounds may then be reduced to thecompounds of this invention of formula II, by the methods as describedabove.

Alternatively, the compounds of formula (II) may be prepared, using thesame conditions, from compounds of the following formula: ##STR12##wherein R is as defined above and R₅ is selected from the groupconsisting of C₁ -C₆ alkyl, hydrogen, C₃ -C₆ cycloalkyl, and phenyl.

The compounds of formula II, above, may also be prepared by thecyclization of a compound of the formula: ##STR13## wherein R is asdefined above, and W is a suitable leaving group such as bromide,chloride, iodide, methanesulfonyloxy or p-toluenesulfonyloxy groups,with sodamide, wherein R is hydrogen, or with a compound of the formulaXNH₂ wherein X is as defined above, in a solvent such as ethanol ormethanol, at a temperature of from about 0° to about 150° C. An acidbinding agent such as sodium carbonate, ethyldiisopropylamine and thelike are usually employed.

Compounds of formula III may be prepared by the reaction of diols of theformula: ##STR14## wherein R is as defined above, with phosphorouspentabromide, hydrogen bromide, hydrogen iodide, hydrogen chloride-zincchloride, thionyl chloride, phosphorous pentachloride, methanesulfonylchloride, or p-toluenesulfonyl chloride.

The above diols may be prepared from compounds of the formula: ##STR15##wherein R is as defined above and R₃ is selected from the groupconsisting of hydrogen and C₁ -C₆ alkyl, by reaction with diborane,lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydridein an aprotic solvent such as ether, benzene or tetrahydrofuran at atemperature of from about 0° to about 80° C. for a period of from aboutone to about six hours. The reaction mixture is cooled and the productis liberated by hydrolysis of the reaction product using acids or basesin a manner known to those skilled in the art.

These cyclopropane-1,2-dicarboxylic esters are also useful intermediatesin other procedures for the compounds of this invention. For example,when saponified to the cyclopropane-1,2-dicarboxylic acids they areuseful for the cyclopropane-1,2-dicarboximides (I), as described above;and the cyclopropane-1,2-dicarboxylic acids are also useful inresolution procedures (as described below).

The diesters above, wherein R₃ is C₁ -C₆ alkyl, may be prepared byreaction of a bromoester of the formula: ##STR16## wherein R₃ is asdescribed above, with an acrylic ester of the formula:

    RCH═CRCOOR.sub.3

wherein R and R₃ are as described above, using a suitable base such aslithium hydride, sodium hydride, sodium methoxide, or potassiumtert-butoxide in a suitable aprotic solvent such as ether, benzene, ortetrahydrofuran, as described in U.S. Pat. No. 3,344,026. The desiredcis-isomers are the predominant products of this reaction.

Certain cis-diacids of the formula: ##STR17## wherein R is as describedabove may be prepared by heating the following compounds with a suitablebase such as sodium hydroxide or potassium hydroxide in a suitablesolvent such as methanol, ethanol or water at a temperature of fromabout 30° to about 100° C., from about 3 to about 18 hours, followed byliberation of the free diacid with a suitable mineral acid such ashydrochloric acid or sulfuric acid: ##STR18## wherein R is as definedabove and U and V are the same or different and are selected from thegroup consisting of --CO₂ R₄, where R₄ is selected from the groupconsisting of C₁ -C₆ alkyl, and cyano.

Compounds of the previous structure wherein U is cyano and V is --CO₂ R₃may be prepared by the reaction of a bromoester of the formula:##STR19## wherein R₄ is as described above, and an acrylonitrile of theformula RHC═CRCN, in a manner as described above for the preparation ofthe diesters. Compounds of the previous structure wherein U is --CO₂ R₄and V is cyano may be prepared by the reaction of abromophenylacetonitrile of the formula: ##STR20## with an acrylic esteris described above.

A lactam of the formula: ##STR21## wherein R is as defined above may beprepared from the above described cyanoesters of the formula: ##STR22##wherein R and R₃ are as described above by reduction with diborane in asolvent such as tetrahydrofuran, at from about 0° to about 60° C. forabout 1 to about 3 hours, followed by reaction of the intermediatereduction product with a mineral acid such as 6 N hydrochloric acid.Similarly, a lactam of the formula: ##STR23## wherein R is as definedabove, may be prepared from a cyano-ester of the formula: ##STR24##wherein R and R₃ are as described above, by reduction in a manner aspreviously described.

By another alternative route, a compound of formula (II) of thisinvention wherein R is hydrogen may be prepared by the reaction of3-phenyl-3-pyrroline of the formula: ##STR25## wherein R and X are asdescribed above, with a compound of the formula CH₂ I₂ under theconditions of the Simmons-Smith reaction as described by N. Kawabuton,et al., J. Amer. Chem. Soc., 98, 2676 (1976).

Additionally, new compounds of the present invention of the formula:##STR26## wherein R and X are as defined above, and R₇ is selected fromthe group consisting of C₁ -C₃ alkyl, with the proviso that the phenylmoiety may not be substituted with hydroxy, acetamido or amino, may beprepared from a lactam of the formula: ##STR27## wherein R and X are asdescribed above, by reaction with a organometallic compound such asmethyl lithium, followed by reaction of the intermediate enamine withsodium borohydride [M. Takeda, et al., Chem. Pharm. Bull., 24, 2312(1976)].

In a like manner a compound of the formula: ##STR28## wherein R, R₇, andX are as described previously, may be prepared from a compound of theformula: ##STR29## wherein R and X are as described above.

The above lactams, wherein X is other than hydrogen, and is as describedabove, may be prepared from the corresponding lactams wherein X ishydrogen by alkylation of the union of the lactam as described above forthe alkylation of the corresponding imides.

Alternatively, a compound of formula (I) above may be reacted with aGrignard reagent, R'Mg Halogen, such as methylmagnesium iodide, orethylmagnesium bromide in an aprotic solvent such as ether, benzene ortetrahydrofuran, at from about 0° to about 25° C., for about 1 to about18 hours, followed by hydrolysis of the reaction product with water togive a hydroxylactam of the formula: ##STR30## wherein R, R₇ and X areas defined above. The above hydroxylactam may be reduced to a compoundof this invention of the formula (IV) in the general manner describedabove.

Amides of the formula: ##STR31## may be prepared from compounds offormula (II), above, wherein R is hydrogen, by reaction with acidhalides of the formula R₅ COX, where X is chlorine, bromine or theimidazolyl group, or with anhydrides of the formula (R₅ CO)₂ O, whereinR₅ is as defined above, in a suitable solvent such as pyridine, water orbenzene, and using an acid binding agent such as sodium hydroxide,triethylamine, or sodium carbonate, at from about 0° to about 80° C.,for about 30 minutes to about 18 hours.

Alternatively, new compounds of the present invention of formula (II),wherein R is other than hydrogen, as described above, may be preparedfrom a compound of formula (II) where R is hydrogen, by an alkylationreaction with a compound of the formula R₅ CH₂ W where R₅ is as definedabove, or a p-fluorobenzoylethyl group, or 4,4-bis(p-fluorophenyl)propylgroup in a solvent such as methanol, ethanol, or ether, using an acidbinding agent such as sodium carbonate, at from about 25° to about 80°C. for about 1 to about 18 hours.

Alternatively, an imide of formula (I) wherein R is hydrogen may bealkylated with a compound of the formula R₅ CH₂ W as described above, byreaction of the imide with a strong, non-nucleophilic base such assodium hydroxide or potassium tert-butoxide in a solvent such asN,N-dimethylformamide, followed by combination with the alkylatingagent. The alkylating agent may also be a compound of the formula R₅CHWR₆ where R₅ and W are as described above, and R₆ is selected from thegroup consisting of C₁ -C₆ alkyl.

The novel compounds of this invention exist as optical isomers whichcomprise racemic dextrorotatory and levorotatory forms. This inventioncontemplates all such isomeric forms. The optical isomers of thecompounds of this invention may be prepared by a variety of resolutionprocedures.

By one method, a cis-diacid of the formula: ##STR32## wherein R is asdefined above, may be combined with an optically active amine such as(-)-α-(1-naphthyl)ethylamine in a suitable solvent such as methanol,ethanol, acetone, tetrahydrofuran, or acetonitrile to give a saltcomprised of one molecular equivalent of the (+)-diacid and onemolecular equivalent of the above (-)-amine. In some cases, andparticularly when the phenyl moiety is substituted with one or morealkyl groups, and specifically where the aryl moiety is the p-tolylgroup and both R are hydrogen, it is advantageous to use atetrahydrofuran-ether mixture as the solvent.

The above racemic diacid can also be combined with (-)-2-amino-1-butanolin a suitable solvent, as previously described, to give a salt whereinthe acid moiety is the (+)-diacid. The above salts can be converted tothe corresponding (+)-diacid by combination of the above salts with asuitable base such as sodium hydroxide, potassium hydroxide, ammoniumhydroxide or potassium carbonate followed by acidification of theaqueous solution with a suitable acid such as hydrochloric acid orsulfuric acid. For the (-)-diacid, a cis-diacid of the formula:##STR33## wherein R is as described above, may be combined with anoptically active amine such as brucine, or (+)-α-(1-naphthyl)-ethylamineor (+)-2-amino-1-butanol in a suitable solvent, as described above, togive salts wherein the acid moiety is the (-)-diacid.

These salts can be converted to the corresponding (-)-diacid in themanner described above. The (+) or (-) diacids described above may beconverted to the compounds: ##STR34## wherein R and X are as definedabove, by the methods described above. These imides may be reduced bythe methods described above to give the optically active forms of thecompounds of this invention: ##STR35## wherein R and X are as definedabove.

Alternatively, a racemic compound of the formula: ##STR36## wherein Rand X are as defined above, may be combined with an optically activeacid such as (+) or (-)-mandelic acid, (+) or (-)-tartanic acid, (+) or(-)-di-O-benzoyltartanic acid or (+) or (-)-di-O-(p-toluoyl)tartanicacid in a suitable solvent such as methanol, ethanol, acetone,acetonitrile, or tetrahydrofuran to give a salt. Combination of theabove salt with a suitable acid such as hydrochloric acid or sulfuricacid, with subsequent basification of the aqueous solution with a basesuch as sodium hydroxide, potassium hydroxide, ammonium hydroxide orsodium carbonate, gives the compound of this invention: ##STR37##wherein R and X are as defined above, in an optically active form.

Among the azabicyclohexanes included within the scope of this inventionare:

1-(p-Chlorophenyl)-3-azabicyclo[3.1.0]hexane

1-Phenyl-3-azabicyclo[3.1.0]hexane

3-Methyl-1-phenyl-3-azabicyclo[3.1.0]hexane

1-(m-Chlorophenyl)-3-azabicyclo[3.1.0]hexane

1-(m-Fluorophenyl)-3-azabicyclo[3.1.0]hexane

1-(p-Chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]-hexane

3-Benzyl-1-phenyl-3-azabicyclo[3.1.0]hexane

3-Cyclopropylmethyl-1-phenyl-3-azabicyclo[3.1.0]-hexane

3-Phenethyl-1-phenyl-3-azabicyclo[3.1.0]hexane

3-Isopropyl-1-phenyl-3-azabicyclo[3.1.0]hexane

1-(p-Trifluoromethylphenyl)-3-azabicyclo[3.1.0]-hexane

3-(p-Chlorobenzyl)-1-(p-chlorophenyl)-3-azabicyclo-[3.1.0]hexane

3-Allyl-1-phenyl-3-azabicyclo[3.1.0]hexane

3-Ethyl-1-phenyl-3-azabicyclo[3.1.0]hexane

3-Cyclohexylmethyl-1-phenyl-3-azabicyclo[3.1.0]-hexane

1-(p-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane

1-(p-Chlorophenyl)-3-(o-fluorobenzyl-3-azabicyclo-[3.1.0]hexane

1-Phenyl-5-methyl-3-azabicyclo[3.1.0]hexane

3-Methyl-1-(3,4,5-trimethoxyphenyl)-3-azabicyclo[3.1.0]hexane

1-(p-Tolyl-3,6-dimethyl-3-azabicyclo[3.1.0]hexane

3-(2-Naphthylmethyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane

3-(5-Norbornen-2-ylmethyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane

3-Ethyl-1-(p-aminophenyl)-3-azabicyclo[3.1.0]hexane

1-(p-Chlorophenyl)-3-propargyl-3-azabicyclo[3.1.0]-hexane

3-(p-Fluorobenzoyl)-1-phenyl-3-azabicyclo[3.1.0]-hexane

3-(m-Fluorobenzoyl)-1-phenyl-3-azabicyclo[3.1.0]-hexane

3,4-Dichlorophenyl-3-azabicyclo[3.1.0]hexane

1-(m-Methoxyphenyl)-3-methyl-3-azabicyclo[3.1.0-hexane

(+)-Phenyl-3-methyl-3-azabicyclo[3.1.0]hexane

1-(4-Chloro-α,α,α-trifluoro-m-tolyl)-3-azabicyclo-[3.1.0]hexane

3,6-Dimethyl-1-phenyl-3-azabicyclo[3.1.0]hexane

1-(p-Acetamidophenyl)-3-ethyl-3-azabicyclo[3.1.0]-hexane

1-(m-Hydroxyphenyl)-3-methyl-3-azabicyclo[3.1.0]-hexane

1-(p-Nitrophenyl)-3-azabicyclo[3.1.0]hexane

1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride

1-(o-Chlorophenyl)-3-azabicyclo[3.1.0]hexane

The compounds of the present invention are useful as analgesic agents inwarm-blooded animals, as evident from testing by several procedures. Onemethod is a modification of the method of Randall and Selitto [Arch.Int. Pharmacodyn., 111, 409 (1957)]. This test measures the painthreshold of rats whose paws are made sensitive to pressure by theinjection of 0.1 ml of a 20% aqueous suspension of brewers' yeast intothe plantar surface of the left hind paw. Constantly increasing force(16 g/second) is applied to the swollen paw using an Analgesey Meter,Ugo Basile. The pressure is cut off at 250 g of force if there is noresponse (sudden struggle or vocalization). Control rats treated withstarch vehicle respond to a pressure of about 30 g. Pressure-painthresholds are recorded one to several hours after administration of thetest compound (at the estimated time of peak effect) at doses up to 200mg/kg orally. The brewers' yeast is administered two hours beforemeasurement of the pain threshold. Ratios of treated (T)/control (C) arecalculated, and are used to determine screening activity, to estimatepotency by means of dose response experiments, and/or to measureanalgesic efficacy (i.e. the higher the T/C ratio the greater theanalgesic efficacy). For example, test compounds may be considered asactive (significant over parallel controls) when they produce a 100%elevation of the pain threshold (T/C≧2.0 ). An active screening resultmay be followed up by one or more of the following experiments: repeattesting at the same dose for confirmation; testing at a lower dose;determination of duration and time of peak effect; dose-responseestimates of potency; determination of the efficacy ceiling (maximumT/C). using experimental protocols well known to those skilled in theart.

Representative compounds of the present invention also exhibit analgesicactivity when measured by a modification of the method of D. C. Atkinsonand A. Cowan, J. Pharm. pharmacol. 26, 727 (1974).

In this test male, albino Wistar strain rats from Royalhart farms,weighing 120-150 g are deprived of food for about 20 hours. A 40%suspension of brewers' yeast in physiological saline is injected, at aconcentration of 0.25 ml/rat into the plantar surface of the left hindpaw of each rat. Three hours later, at which time an inflammation of theinjected paw has developed, a pre-drug assessment of walking gait ismade for each rat according to the following scoring system:

O=Normal gait in the presence of a severely inflammed paw. There iscontinuous use of the foot pad.

0.5=As above with intermittent mild limping.

1.0=Constant limping, but continuous use of the foot pad.

1.5=Limping with occasional three-legged gait (paw kept off walkingsurface) or intermittent use of digits in combination with foot pad.

2.0=Continuous three-legged gait and/or only the tips of the digitstouch the walking surface. There is no use of the foot pad.

More than 95% of the rats exhibit a gait score of 2 before given a testcompound. Compounds, in a suitable vehicle, are administered orally bygavage in a volume of 0.5 ml/100 g of body weight. One and/or two hourslater a post-drug assessment of walking gait is made as described above.The post-treatment score is then measured and compared with thepretreatment score. These results are used for determination ofscreening activity, for dose response estimates of potency, etc. Forexample, when screening experiments are carried out using 3 animals perdose, the pretreatment score is (6(2.0×3) and a post-treatment score of4 (for 3 animals) may be considered as significant activity overparallel controls. For dose-response estimates, an individual animal maybe considered to show an analgesic effect when there is a ≧50% reversalof the abnormal gait score (≧1.0 post-drug) from the pre-drug score(2.0).

Another method for measuring the activity of the compounds of thepresent invention is the "writhing syndrome" test for analgesic activityas described by Siegmund, et al., Proc. Soc. Exp. Biol. and Med., 95,729 (1957), with modifications. This method is based upon the reductionof the number of writhes following the intraperitoneal injection of onemg/kg of body weight of phenyl-p-quinone in male Swiss albino miceweighing 18-25 gm. The syndrome is characterized by intermittentcontractions of the abdomen, twisting and turning of the trunk, andextension of the hind legs beginning 3 to 5 minutes after injection ofthe phenyl-p-quinone. The test compounds are administered orally at theindicated dose to groups of 2 mice each, 30 minutes before injection ofthe phenyl-p-quinone. The total number of writhes exhibited by eachgroup of mice is recorded for a 3 minute period commencing 15 minutesafter injection of the phenyl-p-quinone. A compound is considered activeif it reduces the total number of writhes in 2 test mice from a controlvalue of approximately 30 per pair to a value of 18 or less.

When representative compounds of the present invention are tested by oneor more of the above described analgesic procedures the results aresummarized in the following Tables (I and II):

                                      TABLE 1                                     __________________________________________________________________________    Analgesic Screening                                                            ##STR38##           Procedure                                                Phenyl              Reversal of                                               Sub-                Abnormal                                                                            Antiwrithing                                                                         Inflamed Paw-                                stituent                                                                             X            Gait (Rat)                                                                          (Mouse)                                                                              Pain (Rat)                                   __________________________________________________________________________    p-Cl   H            A(100)*                                                                             A(50)* A(100)*                                      p-Cl   H (-)-Isomer       A(100)                                              p-Cl   H (+)-Isomer A(50) A(100) A(50)                                        H      H            A(150)                                                                              A(100) A(200)                                       H      Me           A(150)                                                                              A(100) A(200)                                       m-Cl   H            A(50) A(200) A(50)                                        m-F    H                  A(100) A(50)                                        H      H (-)-Isomer       A(100) A(50)                                        H      Me (-)-Isomer      A(50)                                               p-Cl   Me (-)-Isomer      A(100)                                              p-Cl   Me (+)-Isomer                                                                              A(150)                                                                              A(100)                                              p-Cl   Me                 A(100)                                                      ##STR39##   A(200)                                                    H                                                                                     ##STR40##         A(100)                                              p-CF.sub.3                                                                           H            A(150)       A(50)                                        H      Et           A(200)                                                    p-MeO  H            A(100)       A(50)                                        H      H (+)-Isomer A(200)                                                                              A(50)  A(50)                                        3,4-DiCl                                                                             H            A(200)                                                    p-Et   H            A(25)        A(50)                                        m-Me   H            A(50) A(25)  A(50)                                        p-Br   H            A(200)                                                    p-F    H            A(100)                                                                              A(50)  A(50)                                        p-Br                                                                                  ##STR41##   A(200)                                                    m-MeO  Me           A(100)                                                                              A(50)  A(50)                                        H      Me (+)-Isomer                                                                              A(200)                                                    4-Cl-3-CF.sub.3                                                                      H            A(200)                                                    p-NO.sub.2                                                                           H            A(200)                                                    p-Me   H            A(200)                                                                              A(60)  A(50)                                        m-CF.sub.3                                                                           H            A(25)        A(50)                                        3-Br-4-MeO                                                                           H            A(200)                                                    p-Me   H (+)-Isomer A(50) A(25)  A(50)                                        p-Me   H (-)-Isomer       A(100) A(50)                                        p-Me   Me           A(100)       A(50)                                        p-OH   H            A(200)       A(50)                                        p-EtO  H            A(50)                                                     p-Cl   Et                 A(100)                                              H                                                                                     ##STR42##   A(200)                                                    p-Cl                                                                                  ##STR43##   A(200)                                                    H                                                                                     ##STR44##   A(200)                                                    m-MeO  H            A(200)                                                    __________________________________________________________________________     *Active (at indicated dose, mg/kg orally.)                               

TABLE 2 Median Effective Doses

Reversal of abnormal gait in the rat:

ED₅₀ calculated as the 50% level for animals showing an analgesic effectdefined at ≧50% reversal of the abnormal gait score [absorption time(minutes) in parentheses].

Antiwrithing in the mouse:

ED₅₀ calculated as the 50% level for groups of 2 mice showing ananalgesic effect defined as ≦18 writhes per pair.

Inflamed paw-pain in the rat:

ED₅₀ calculated as the 50% level for animals showing an analgesic effectdefined as T/C ≧2.0 [absorption time (minutes) in parentheses].

                                      TABLE 2                                     __________________________________________________________________________    Median Effective Doses                                                         ##STR45##     Procedure                                                                    Reversal of                                                     Phenyl        Abnormal                                                                              Antiwrithing                                                                         Inflamed Paw-                                    Substituent                                                                         X       Gait (Rat)                                                                            (Mouse)                                                                              Pain (Rat)                                       __________________________________________________________________________    p-Cl  H        ˜50(120')                                                                      21     ˜12.5(120')                                p-Cl  H (-)-Isomer    <100                                                    p-Cl  H (+)-Isomer                                                                            25(120')                                                                            18.5   <12.5(120')                                      H     H         70(90')                                                                             <100   >50(120')                                        m-Cl  H        >50(120')                                                                            34     >50(120')                                        m-F   H               21     >50(120')                                        H     H (-)-Isomer    <50    ˜50(120')                                  p-CF.sub.3                                                                          H         38(90')      ˜50(120')                                  p-MeO H         24(90')                                                                             4.4     42(60')                                         H     H (+)-Isomer                                                                          ˜200(120')                                                                             >50(120')                                        p-Et  H         13(90')      ˜50(120')                                  m-Me  H        >50(120')                                                                            17.5   ˜25(120')                                  p-F   H        >50(120')                                                                            34      13.5(120' )                                     p-Me  H         14.3(60')po                                                                         13.2     9.2(60')po                                                     4.2(60')sc    10.1(120')sc                                    m-CF.sub.3                                                                          H        ˜25(120')                                                                             ˜50(120')                                  p-Me  H (+)-Isomer                                                                            8.9(60')                                                                            16     ˜12.5(120')                                p-Me  H (-)-Isomer    ˜100                                                                           >50(120')                                        p-Me  Me        20(90')      ˜25(120')                                  __________________________________________________________________________     *ED.sub.50, mg/kg orally (po), unless otherwise noted (at absorption time     in minutes): sc = subcutaneous administration.                           

Certain compounds of this invention also show anti-anxiety activity bytheir ability to protect warm-blooded animals from convulsions resultingfrom the administration of pentylenetetrazole. Dose levels of the testcompounds are administered orally in a 2% starch vehicle to groups of atleast 4 rats. At the estimated time of peak effect, the rats are treatedintravenously with pentylenetetrazole at a dose of 21 to 23 mg/kg ofbody weight. This dose is estimated to cause clonic seizures in 99% ofunprotected rats. Protection (or lack, thereof) against these seizuresis measured in each animal. When a test compound is screened in a groupof 4 rats, protection in 2, 3 or 4 animals is considered significantactivity over parallel controls (>25% protection). In follow-up teststhe effective dose of the test compounds for protection of 50% of theanimals (ED₅₀) may be calculated by the method of D. H. Finney inStatistical Methods in Biological Assay, Second Edition, HofnerPublishing Co., New York pp. 456-457, (1964) or by the method of J. T.Litchfield and J. Wilcoxon, Pharmacol. and Exp. Ther., 96, 99 (1949). Ithas been reported [R. T. Hill and D. H. Tedeschi, "Animal Testing andScreening Procedures in Evaluating Psychotropic Drugs", in AnIntroduction to Psychopharmacology, Eds. R. R. Rech and K. E. Moore,Raven press, New York, pp 237-288 (1971)] that there is a high degree ofcorrelation between anti-convulsant effects in rodents and anti-anxietyeffects in higher warm-blooded animals. The results of this test onrepresentative compounds of the present invention appear in Table III.

                  TABLE 3                                                         ______________________________________                                                             Median Effective Dose                                    Compound             (mg/kg) oral                                             ______________________________________                                        1-(p-Chlorophenyl)-3-azabicyclo-                                              [3.1.0]hexane hydrochloride  15                                               (-)-1-(p-Chlorophenyl)-3-azabicyclo-                                          [3.1.0]hexane hydrochloride  24                                               1-Phenyl-3-azabicyclo[3.1.0]hexane                                            hydrochloride                103                                              1-(p-Fluorophenyl)-3-azabicyclo-                                              [3.1.0]hexane hydrochloride  15                                               3-Cyclopropylmethyl-1-phenyl-3-aza-                                           bicyclo[3.1.0]hexane hydrochloride                                                                 Active  (50)                                             ______________________________________                                    

The azabicyclohexanes of the present invention can be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food or the diet. For oral therapeuticadministration, the active compounds of this invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, and the like. Suchcompositions and preparations should contain at least 0.1% of activecompound. The percentage in the compositions and preparations may, ofcours, be varied and may conveniently be between about 5% to about 75%or more of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions or preparations is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 10 and 400 milligrams of active compound. Amost preferred composition would be an oral dosage unit form containingfrom about 50 to 250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, aliginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose, or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills or capsules may containthe active compounds, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor. Of course, any material used in preparing any dosage unitform should be pharmaceutically pure and substantially non-toxic in theamounts employed.

Compositions having the desired clarity, stability, and adaptability forparental use are obtained by dissolving from 0.10% to 10.0% by weight ofthe azabicyclohexane in a vehicle consisting of a mixture ofnon-volatile, normally liquid polyethylene glycols which are soluble inboth water and organic liquids and which have molecular weights of fromabout 200 to about 1500. Such mixtures of polyethylene glycols arecommercially available and are usually obtained by condensing glycolwith ethylene oxide. Although the amount of azabicyclohexane dissolvedin the above vehicle may vary from 0.10% to 10.0% by weight, it ispreferred that the amount employed be from about 3.0% to about 9.0% byweight. Although various mixtures of the aforementioned nonvolatilepolyethylene glycols may be employed, it is preferred to use a mixtureof non-volatile polyethylene glycols having an average molecular weightof about 400. Such a mixture is usually referred to as polyethyleneglycol 400. A preferred embodiment comprises a clear solution of fromabout 3.0% to about 9.0% by weight of the azabicyclohexane dissolved inan aqueous solution of polyethylene glycol 400. In addition to theazabicyclohexane, the parenteral solutions may also contain variouspreservatives which may be used to prevent bacterial and fungalcontamination or chemical degradation.

SPECIFIC EXAMPLES

The following specific examples describe in detail the preparation ofrepresentative compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1 Preparation of Racemic1-(p-Chlorophenyl)-3-azabicyclo[3.1.0]-hexane hydrochloride

A solution of 2 g of diethyl1-(p--chlorophenyl)-cis-1,2-cyclopropanedicarboxylate (U.S. Pat. No.3,344,026, Ex. 1) in 25 ml of ethanol is treated with 13.5 ml of 1 Npotassium hydroxide solution. The reaction mixture is refluxed for 3.5hours and then is allowed to stand at room temperature overnight. Theethanol is removed under reduced pressure and the aqueous solution isextracted with ether to remove a small amount of mineral oil. Theaqueous solution is treated with 13.5 ml of 1 N hydrochloric acid and 2ml of 6 N hydrochloric acid. The oily aqueous mixture is extracted fourtimes with chloroform. The chloroform solution is dried, decolorized,and concentrated under reduced pressure to give a yellow solid. Tworecrystallizations from ethyl acetate-petroleum ether (30°-70° C.) gives0.85 g of a white solid,1-(p-chlorophenyl)-cis-1,2-cyclopropanedicarboxylic acid, m.p. 162°-163°C.

A 5.7 g portion of the above acid and 2.02 g of urea in 200 ml of xyleneis refluxed for 22 hours, cooled, diluted with benzene and washed withwater. The organic layer is diluted with chloroform, dried, concentratedunder reduced pressure and recrystallized from ethyl acetate andpetroleum ether to give1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide.

To a stirred solution f 30 ml of sodium bis(2-methoxyethoxy)aluminumhydride (70% benzene solution) is added dropwise a solution of 2.2 g of1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 100 ml of benzeneover a 30 minute period at room temperature under nitrogen atmosphere.The reaction vessel is warmed slightly to maintain solution. The clearyellow solution is then heated to reflux under nitrogen atmosphere forone hour. The solution is cooled and the excess reagent decomposed with5 N sodium hydroxide. Water is added to the mixture and the benzenephase is separated. The aqueous phase is extracted with ether and theether extracts are combined with the benzene phase and dried overmagnesium sulfate. This organic phase is evaporated under reducedpressure to give a viscous liquid, which crystallizes to a tackyoff-white solid consisting of the racemic base1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane. This solid is dissolved inethanol, acidified with ethanolic hydrogen chloride, and ether is addedproducing off-white cyrstals of the hydrochloride. This isrecrystallized from ethanol giving off-white crystals, mp 215°-217° C.

In a like manner, reductions of the following imides with sodiumbis-(2-methoxyethoxy)aluminum hydride yield the corresponding reducedproducts.

    ______________________________________                                        Imide            Reduction Product                                            ______________________________________                                        1-phenyl-2-methyl-1,2-                                                                         1-phenyl-5-methyl-3-azabicyclo-                              cyclopropanedicarboximide                                                                      [3.1.0]hexane hydrochloride,                                 (U.S. 3,166,571-Example 15)                                                                    m.p. 161°-163° C.                              N-methyl-1-(3,4,5-tri-                                                                         3-methyl-1-(3,4,5-trimethoxy-                                methoxyphenyl)-1,2-cyclo-                                                                      phenyl)-3-azabicyclo[3.1.0]-                                 propanedicarboximide                                                                           hexane hydrochloride, m.p. 243°-                      (U.S. 3,166,571-Example 4)                                                                     245° C.                                               1-(p-tolyl)-3,N-dimethyl-                                                                      1-(p-tolyl)-3,6-dimethyl-3-                                  1,2-cyclopropanedicarbox-                                                                      azabicyclo[3.1.0]hexane                                      imide                                                                         (U.S. 3,166,571-Example 11)                                                   ______________________________________                                    

EXAMPLE 2 Preparation of(-)-1-(p-Chlorophenyl)-3-azabicyclo[3.1.0]-hexane hydrochloride

To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminumhydride (70% benzene solution) is added dropwise a solution of 6.6 g of(-)-1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide (U.S. Pat. No.3,892,772) in 500 ml. of benzene over a three hour period at roomtemperature under nitrogen. The clear yellow solution is heated atreflux for 90 minutes under nitrogen and then stored overnight at roomtemperature. The excess hydride reagent is decomposed by the cautiousaddition of 25 ml of 5 N sodium hydroxide. The mixture is then dilutedwith 200 ml of water. The benzene phase is separated and the aqueousphase is extracted with chloroform. The combined benzene and chloroformphases are dried over magnesium sulfate and concentrated under reducedpressure to give (-)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as ayellow solid. This solid is dissolved in ethanol and acidified with 10ml of 2.3 N ethanolic hydrogen chloride. The addition of ether causesthe precipitation of the hydrochloride of this base as a solid which iscollected and dried giving white crystals, m.p. 197°-200° C. [α]_(D)^(CH).sbsp.3^(OH) =-67°.

EXAMPLE 3 Preparation of(+)-1-(p-Chlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride

A 192.5 g portion of racemiccis-1-(p-chlorophenyl)-1,2-cyclopropanedicarboxylic acid (U.S. Pat. No.3,892,772) and 142 g of (-)-2-aminobutanol in 1600 ml of acetone isallowed to stand for 48 hours, filtered and washed with acetone giving asolid. This solid is dissolved in 460 ml of warm water and acidified.The solid is filtered and air dried. A 107.5 g portion of this crude(+)-diacid and 79.3 g of (-)-2-aminobutanol in 892 ml of acetone areallowed to stand several hours. The solid is filtered, dried, dissolvedin 200 ml of warm water, acidified with concentrated hydrochloric acid,cooled and filtered. This solid is recrystallized from acetonitrilegiving (+)-cis-1-(p-chlorophenyl)-1,2-cyclopropanedicarboxylic acid,[α]_(D) ^(CH).sbsp.3^(OH) =+180°.

A 10.5 g portion of this (+)-diacid and 3.9 g of urea in 325 ml ofxylene is stirred and then refluxed for 71/2 hours and then allowed tostand overnight. Distilling off the xylene, cooling and filtrationproduces a white solid which is recrystallized from ethanol giving(+)-1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide [α]_(D)^(CH).sbsp.3^(OH) =+63°.

To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminumhydride (70% benzene solution) is added dropwise a solution of 4.5 g of(+)-1-(p-chlorophenyl)-1,2-cyclopropanedicarboxamide in 400 ml ofbenzene during a 45 minute period with stirring at room temperatureunder nitrogen. The clear yellow solution is heated at reflux undernitrogen for 90 minutes and stored overnight at room temperature. Theexcess hydride reagent is decomposed by the cautious addition of 25 mlof 5 N sodium hydroxide. The mixture is diluted with 200 ml of water andthe benzene phase is removed. The aqueous phase is extracted withchloroform. The combined benzene and chloroform phases are dried overmagnesium sulfate and concentrated under reduced pressure to give(+)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as a tacky yellowsolid. This solid is dissolved in ethanol and acidified with 20 ml of2.3 N ethanolic hydrogen chloride. A 200 ml volume of ether is added andcrystals form. These are recrystallized from acetonitrile to give thehydrochloride as white crystals, m.p. 190°-192° C.; [α]_(D)^(CH).sbsp.3^(OH) =+63° C.

EXAMPLE 4 Preparation of Racemic 1-Phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminumhydride (70% benzene solution) is added dropwise a solution of 6.6 g of1-phenyl-1,2-cyclopropanedicarboxamide (U.S. Pat. No. 3,166,571-Ex. 8)in 400 ml of benzene, during one hour at room temperature undernitrogen. The reaction mixture is then heated at reflux under nitrogenfor 90 minutes. The excess hydride reagent is decomposed by the cautiousaddition of 25 ml of 10 N sodium hydroxide. The mixture is diluted with200 ml of water and the benzene phase is separated. The aqueous phase isextracted with chloroform and the combined organic extracts are driedover magnesium sulfate. The solution is concentrated under reducedpressure to give a brown liquid which is dissolved in ethanol andacidified with 5 ml of 2.3 N ethanolic hydrogen chloride. The additionof ether precipitates a solid which is recrystallized from acetonitrileto give white crystals, mp 166°-168° C.

EXAMPLE 5 Preparation of Racemic3-Methyl-1-phenyl-3-azabicyclo[3.1.0]-hexane hydrochloride

To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminumhydride (70% benzene solution) is added dropwise a solution of 5.5 g ofN-methyl-1-phenyl-1,2-cyclopropanedicarboxamide (U.S. Pat. No.3,166,571-Ex. 1) in 400 ml of benzene over a one hour period at roomtemperature under nitrogen. The mixture is heated at reflux undernitrogen for 90 minutes. The excess hydride reagent is decomposed by thecautious addition of 25 ml of 10 N sodium hydroxide and then diluted to200 ml with water. The benzene phase is separated and the aqueous phaseis extracted with chloroform. The combined organic phases are dried overmagnesium sulfate and concentrated under reduced pressure giving aliquid. The liquid is dissolved in ethanol and acidified with 15 ml of2.3 N ethanolic hydrogen chloride. The addition of ether causes theformation of a solid which is recrystallized from isopropylalcohol-hexane giving white crystals, m.p. 158°-160° C.

EXAMPLE 6 Preparation of 1-(m-Chlorophenyl)-3-azabicyclo[3.1.0] hexanehydrochloride

A 53.6 g portion of ethyl m-chlorophenylacetate (prepared byesterification of the corresponding acid), 51.5 g of N-bromosuccinimideand one gram of benzoyl peroxide in 1.25 liters of carbon tetrachlorideis stirred with a Nichrome metal stirrer and refluxed for 20 hours. Themixture is cooled, filtered and concentrated to an orange oil. Vacuumdistillation yields the product ethyl α-bromo-m-chlorophenylacetate.

To a stirred suspension of 4.4 g of sodium hydride in 500 ml of etherunder nitrogen is added 0.5 ml of ethanol. A mixture of 27.8 g of theabove ester, 10 g of ethyl acrylate and one ml of ethanol is addeddropwise and the mixture is stirred at room temperature overnight.Ethanol is added to decompose the unreacted sodium hydride and themixture is washed with 100 ml of water, 50 ml of 1 N hydrochloric acid,three times with dilute sodium bicarbonate and finally with 100 ml ofwater. The product is dried and concentrated under reduced pressure to ayellow liquid, 1-(m-chlorophenyl)-1,2-cyclopropanedicarboxylic aciddiethyl ester.

A 22 g portion of this diester in 150 ml of ethanol and 150 ml of 1 Npotassium hydroxide is refluxed for 3.5 hours and then allowed to standat room temperature overnight. The mixture is concentrated and extractedwith ether. The aqueous phase is acidified with 1 N hydrochloric acid,extracted three times with chloroform, dried and concentrated underreduced pressure to a yellow oil which is crystallized from ethylacetate-petroleum ether to givecis-1-(m-chlorophenyl)-1,2-cyclopropanedicarboxylic acid as a whitesolid.

A 5.7 g portion of this acid and 2.02 g of urea in 200 ml of xylene isrefluxed for 22 hours, cooled, diluted with benzene and washed withwater. The organic layer is diluted with chloroform, dried, concentratedunder reduced pressure, and recrystallized from ethyl acetate andpetroleum ether to give1-(m-chlorophenyl)-1,2-cyclopropanedicarboximide.

To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminumhydride (70% benzene solution) is added dropwise a solution of 4.0 g of1-(m-chlorophenyl)-1,2-cyclopropanedicarboximide in 400 ml of benzeneduring 1 hour at room temperature under nitrogen. The reaction is heatedat reflux under nitrogen for 90 minutes. The excess hydride reagent isdecomposed with 25 ml of 10 N sodium hydroxide and the mixture isdiluted with 200 ml of water. The benzene phase is removed and theaqueous phase is extracted with chloroform. The combined organic phasesare dried over magnesium sulfate and concentrated under reduced pressureto give a viscous orange-brown liquid. This liquid is dissolved inethanol and acidified with 2.3 N ethanolic hydrogen chloride. Theaddition of ether precipitates a solid which is recrystallized fromisopropanol to give 1-(m-chlorophenyl)-3-azabicyclo[3.1.0]-hexanehydrochloride as white crystals, mp 182°-184° C.

EXAMPLE 7 Preparation of 1-(m-Fluorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride

A 46.2 g portion of 1-(m-fluorophenyl)acetic acid is dissolved in 120 mlof ethanol. A 12 ml portion of sulfuric acid is added, the mixture isrefluxed for 4.5 hours and then allowed to stand at room temperatureovernight. A 400 ml portion of water is added and the mixture isextracted three times with ether, dried over magnesium sulfate andconcentrated under reduced pressure to a liquid. Vacuum distillationproduces ethyl 1-(m-fluorophenyl)-acetate.

A mixture of 49.3 g of ethyl 1-(m-fluorophenyl)-acetate, 53 g ofN-bromosuccinimide and 0.95 g of benzoyl peroxide in 1.6 liters ofcarbon tetrachloride is refluxed and stirred with a Nichrome metalstirrer for 24 hours, concentrated to an orange oil and vacuum distilledgiving ethyl α-bromo-1-(m-fluorophenyl)acetate.

To a suspension of 11 g of sodium hydride in mineral oil in one liter ofether under nitrogen is added dropwise, with stirring a mixture of 65 gof ethyl α-bromo-1-(m-fluorophenyl)acetate, 25 g of ethyl acrylate and 2ml of ethanol. The temperature is maintained at 25°-29° C. with stirringovernight. The mixture is cooled, a few ml of ethanol is added todecompose the unreacted sodium hydride and the mixture is washedsuccessively with water, 1 N hydrochloride acid, dilute sodiumbicarbonate and saturated sodium chloride solution, then concentrated toa liquid which is vacuum distilled giving the diethyl ester of1-(m-fluorophenyl)-1,2-cyclopropanedicarboxylic acid.

A mixture of 20.5 g of the above diester and 160 ml of 1 N potassiumhydroxide in 150 ml of ethanol is refluxed for 3.5 hours andconcentrated. The mixture is acidified with 1 N hydrochloric acid,extracted three times with chloroform, dried and concentrated underreduced pressure to a solid. The solid is recrystallized twice fromethyl acetate-petroleum ether givingcis-1-(m-fluorophenyl)-1,2-cyclopropanedicarboxylic acid.

A stirred mixture of 8.0 g of the above diacid and 2.6 g of urea in 500ml xylene is heated under reflux for 22 hours. The solution is dilutedwith benzene, washed with water and dried over magnesium sulfate. Theorganic layer is concentrated under reduced pressure to give1-(m-fluorophenyl)-1,2-cyclopropanedicarboximide as an off-white solid.

To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminumhydride is added dropwise a solution of 5.6 g of1-(m-fluorophenyl)-1,2-cyclopropanedicarboximide in 400 ml of benzeneduring 90 minutes, under nitrogen at room temperature. The reactionmixture is heated at reflux, under nitrogen for 90 minutes. The excesshydride reagent is decomposed by the cautious addition of 25 ml of 10 Nsodium hydroxide and then the mixture is diluted with 200 ml of water.The benzene phase is removed and the aqueous phase is extracted withchloroform. The combined organic solutions are dried over magnesiumsulfate and concentrated under reduced pressure to give a mixture of anoily solid and a viscous liquid. This mixture is dissolved in ethanoland acidified with ethanolic hydrogen chloride. The addition of ethergives a precipitate which is recrystallized from acetonitrile to give1-(m-fluorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride as graycrystals, mp 140°-146° C.

EXAMPLE 8 Preparation of (-)-1-Phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

To a stirred slurry of 18.7 g of(-)-1-phenyl-1,2-cyclopropanedicarboximide in 500 ml of benzene undernitrogen is added 150 ml of sodium bis(2-methoxyethoxy)aluminum hydride(70% benzene solution) over a period of 10 minutes. The mixture isstirred at room temperature for 2 hours, refluxed for 4 hours and thenallowed to stand at room temperature for 20 hours. A 150 ml portion of10 N sodium hydroxide is added cautiously with stirring. The organiclayer is washed with water, dried over magnesium sulfate and evaporatedunder reduced pressure to a yellow oil. This oil is dissolved in 300 mlof ether. Dry hydrogen chloride gas is bubbled through untilprecipitation ceases and the mixture is filtered giving colorlesscrystals. These are recrystallized from acetonitrile giving pale tancrystals, mp 170°-172° C.

EXAMPLE 9 Preparation of Racemic 1-Phenyl-3-azabicyclo[3.1.0]hexane

Employing 1-phenyl-1,2-cyclopropanedicarboximide (U.S. Pat. No.3,166,571-Ex. 8) in the procedure of Example 8 without the addition ofhydrogen chloride gas there is produced racemix1-phenyl-3-azabicyclo[3.1.0]hexane, bp 130°-133° C. (15 mm).

EXAMPLE 10 Preparation of(-)-3-Methyl-1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride

To a solution of 18.7 g of (-)-1-phenyl-1,2-cyclopropanedicarboxamide in100 ml of anhydrous dimethylformamide is added 5.0 g of sodium hydride(54% in mineral oil) over 15 minutes. The mixture is stirred for 30minutes and then 10 ml of iodomethane is added over 5 minutes. Themixture is allowed to stand for 15 minutes, heated on a steam bath for15 minutes, cooled and poured into 250 ml of water. The mixture isfiltered and the crystals are washed with petroleum ether and air driedgiving (-)-N-methyl-1-phenyl-1,2-cyclopropanedicarboximide.

To a stirred solution of 5.0 g of(-)-N-methyl-1-phenyl-1,2-cyclopropanedicarboximide in 125 ml of benzeneunder nitrogen is added 30 ml of sodium bis(2-methoxyethoxy)aluminumhydride (70% benzene solution) over 10 minutes. The mixture is refluxedfor 5 hours, cooled and 60 ml of 10 N sodium hydroxide is addedcautiously. The organic layer is washed with water, dried over magnesiumsulfate and evaporated under reduced pressure to give an amber oil. Thisoil is dissolved in 250 ml of ether, saturated with hydrogen chlorideand filtered giving colorless crystals. These crystals arerecrystallized from acetonitrile giving colorless crystals, mp194°-196°, [α]_(D) ^(CH).sbsp.3^(OH) =-73°.

EXAMPLE 11 Preparation of(-)-1-(p-Chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride

To a solution of 22.1 g of(-)-1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 100 ml ofanhydrous dimethylformamide is added 5.0 g of sodium hydride (54% inmineral oil) over a 15 minute period. The mixture is stirred for 30minutes and then 10 ml of iodomethane is added over 5 minutes. Thismixture is allowed to stand 15 minutes, heated on a steam bath 15minutes, cooled and poured into 250 ml of water. The crystals arefiltered, washed with petroleum ether and air dried giving colorlesscrystals of(-)-N-methyl-1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide.

To a stirred solution of 11.8 g of the above product in 250 ml ofbenzene under nitrogen is added 60 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) over 10minutes. The mixture is refluxed for 5 hours, cooled and 60 ml of 10 Nsodium hydroxide is added cautiously. The organic layer is washed withwater, dried over magnesium sulfate and evaporated under reducedpressure to an amber oil. The oil is dissolved in 250 ml of ether,saturated with hydrogen chloride and filtered to give colorlesscrystals. Recrystallization from acetonitrile gives colorless crystals,mp 211°-212° C., [α]_(D) ^(CH).sbsp.3^(OH) =-68°.

EXAMPLE 12 Preparation of(+)-1-(p-Chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride

To a stirred solution of 11.08 g of(+)-1-(p-chlorophenyl-1,2-cyclopropanedicarboximide in 50 ml ofanhydrous dimethylformamide is added 2.5 g of sodium hydride (54% inmineral oil) over 15 minutes under nitrogen. The mixture is stirred for30 minutes and 5 ml of iodomethane is added over 5 minutes. The mixtureis allowed to stand 15 minutes, is heated on a steam bath 15 minutes,cooled and poured into 125 ml of water. The mixture is filtered, washedwith petroleum ether and dried giving colorless crystals of(+)-N-methyl-1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide.

To a stirred solution of 3.92 g of(+)-N-methyl-1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 100 mlof benzene, under nitrogen, is added 20 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution), during 10minutes. The mixture is stirred for 2 hours at room temperature and thenrefluxed for 2 hours. A 20 ml portion of 10 N sodium hydroxide is addedcautiously. The benzene layer is washed with water, dried over magnesiumsulfate and evaporated under reduced pressure giving an oil. The oil isdissolved in 200 ml of ether and saturated with dry hydrogen chloridegiving a colorless crystalline cake which is recystallized fromacetonitrile to give(+)-1-(p-chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochlorideas pale tan crystals, mp 209°-210° C., [α]_(D) ^(CH).sbsp.3^(OH) =+67°.

EXAMPLE 13 Preparation of Racemic1-(p-Chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride

To a stirred solution of 44.2 g of racemic1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 200 ml of anhydrousdimethylformamide is added 10.0 g of sodium hydride (50% in mineral oil)over a 5 minute period. A 20 ml portion of iodomethane is added slowlywith stirring over 5 minutes. The mixture is then heated on a steam bathfor 30 minutes, cooled and poured into 500 ml of water. The solid iscollected by filtration and recrystallized from heptane-ethyl acetategiving colorless crystals of racemicN-methyl-1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide.

To a stirred solution of 11.8 g of the above product in 250 ml ofbenzene, under nitrogen, is added 60 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) over 10minutes. After standing for 16 hours the mixture is refluxed for 4hours, cooled and 60 ml of 10 N sodium hydroxide is cautiously added.The organic layer is dried over sodium sulfate, then magnesium sulfate,filtered and evaporated under reduced pressure to give the free base asa pale yellow oil. The oil is dissolved in 200 ml of ether and saturatedwith dry hydrogen chloride gas. The solid is recovered and crystallizedfrom acetonitrile giving pale tan plates, mp 180°-182° C.

EXAMPLE 14 Preparation of 3-Benzyl-1-phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

To 37.4 g of 1-phenyl-1,2-cyclopropanedicarboximide in 200 ml ofanhydrous dimethylformamide is added 10 g of sodium hydride (50% inmineral oil) with stirring. A 25.4 ml portion of benzyl chloride isadded dropwise. A 20 mg portion of potassium iodide is added. Themixture is stirred at room temperature for 2 hours and then poured intoone liter of water producing a gummy residue which is treated withpetroleum ether to produceN-benzyl-1-phenyl-1,2-cyclopropanedicarboximide as pale yellow crystals.

To a stirred solution of 13.87 g of the above product in 250 ml ofbenzene, under nitrogen, is added 60 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) over aperiod of 10 minutes. The mixture is refluxed for 5 hours, cooled and 60ml of 10 N sodium hydroxide is added cautiously. The benzene layer iswashed with water, dried over magnesium sulfate and evaporated underreduced pressure to an amber oil. The oil is dissolved in ether, dryhydrogen chloride gas is added and the solid is recovered andrecrystallized from isopropyl alochol giving colorless crystals, mp194°-196° C.

EXAMPLE 15 Preparation of3-Cyclopropylmethyl-1-phenyl-3-azabicyclo[3.1.0]-hexane hydrochloride

To a stirred slurry of 61.2 g of 1-phenyl-1,2-cyclopropanedicarboximide(U.S. Pat. No. 3,166,571-Example VIII) in 2 liters of benzene is added400 ml of sodium bis(2-methoxyethoxy)aluminum hydride 70% solution inbenzene under nitrogen. The mixture is stirred at room temperature for 2hours, refluxed for 4 hours and then stirred at room temperature for 20hours. A 400 ml portion of 10 N sodium hydroxide is added cautiouslywith stirring. The organic layer is washed twice with dilute sodiumhydroxide and then with water, dried over magnesium sulfate andevaporated to give an amber oil. This oil is dissolved in dilutehydrochloric acid, washed with ether, filtered and the filtrate madebasic with sodium hydroxide. The basic filtrate is extracted withbenzene, dried over magnesium sulfate, filtered and evaporated to give1-phenyl-3-azabicyclo[3.1.0]hexane as an amber oil. To a solution of15.9 g of 1-phenyl-3-azabicyclo[3.1.0]hexane in 100 ml of benzene and 20ml of triethylamine is added 11.0 g of cyclopropanecarboxylic acidchloride in 20 ml of benzene over 5 minutes. The mixture is stirred for30 minutes and 50 ml of water is added. The benzene layer is extractedwith dilute sodium bicarbonate followed by dilute hydrochloric acid andthen water, dried over magnesium sulfate and evaporated to give theproduct 3-cyclopropylcarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexane as abrown oil.

To a solution of 11.35 g of3-cyclopropylcarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexane (preparedabove) in 100 ml of benzene is added 25 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) withstirring. The mixture is allowed to stand for 18 hours, is refluxed for2 hours, cooled and 25 ml of 10 N sodium hydroxide is slowly added. Theorganic layer is washed with saturated sodium chloride, dried overmagnesium sulfate and evaporated to a brown oil. This oil is dissolvedin ether and dry hydorgen chloride gas is bubbled in producing pinkcyrstals. These crystals are recrystallized from isopropyl alcoholgiving pink crystals, mp 164°-165° C.

In a like manner 1-(p-tolyl)-3-azabicyclo[3.1.0]-hexane (Example 36) isreacted with cyclopropanecarbonyl chloride to give3-cyclopropanecarbonyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane which isreduced as above to give3-cyclopropylmethyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochlorideas colorless crystals, m.p. 180°-182° C.

EXAMPLE 16 Preparation of 3-Phenethyl-1-phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

To a stirred solution of 9.35 g of1-phenyl-1,2-cyclopropanedicarboximide in 50 ml of dimethylformamide isadded 2.5 g of sodium hydroxide (50% in mineral oil) over 5 minutes.This mixture is warmed and stirred for 1/2 hour, 0.1 g of potassiumiodide is added and then 9.25 g of phenethyl bromide is added. Themixture is stirred 1/2 hour, heated on a steam bath 15 minutes, stirredat room temperature 15 minutes and then poured into one liter of watermade acidic with acetic acid. The mixture is extracted with methylenechloride and this solution is combined with 50 g of magnesium silicateand evaporated under reduced pressure. The residual powder is applied toa magnesium silicate column and elution with one liter of petroleumether, 500 ml of methylene chloride, one liter of chloroform andevaporation produces N-phenethyl-1-phenyl-1,2-cyclopropanedicarboximideas a colorless oil.

To a solution of 5.80 g of the above compound in 50 ml of benzene isadded 10 ml of sodium bis(2-methoxyethoxy)-aluminum hydride (70% benzenesolution) with stirring. The mixture is allowed to stand 18 hours, isrefluxed 2 hours, cooled and treated with 10 ml of 10 N sodium hydroxideas described in Example 15, yielding the crystalline product, mp207°-209° C.

EXAMPLE 17 Preparation of 3-Isopropyl-1-phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of 20.6 g of 1-phenyl-1,2-cyclopropanedicarboxylic acid and 15g of 1,3-diisopropylurea in 500 ml of xylene is refluxed for 6 hours,filtered and the solvent removed under reduced pressure giving an oil.The oil is absorbed on magnesium silicate in 500 ml of methylenechloride. The solvent is evaporated leaving a powder. The powder isadded to magnesium silicate on a Buchner funnel and eluted with 500 mlof petroleum ether and then one liter of methylene chloride. Themethylene chloride is evaporated givingN-isopropyl-1-phenyl-1,2-cyclopropanedicarboximide as a colorless oil.

To a solution of 9.17 g of the above product in 100 ml of benzene isadded 20 ml of sodium bis(2-methoxyethoxy)-aluminum hydride (70% inbenzene) with stirring. The mixture is allowed to stand for 18 hours, isrefluxed for 2 hours, cooled and 20 ml of 10 N sodium hydroxide isslowly added, followed by 30 ml of 5 N sodium hydroxide. The organiclayer is extracted with dilute hydrochloric acid. The aqueous extract ismade basic with sodium hydroxide, extracted with ether, dried overmagnesium sulfate and dry hydrogen chloride gas is bubbled in producinga gum which is triturated with ether and crystallized from acetoneyielding tan crystals, mp 141°-144° C.

In a like manner 1-(p-chlorophenyl)-1,2-cyclopropanedicarboxylic acidand 1,3-diphenylurea give N,1-diphenyl-1,2-cyclopropanedicarboximidewhich is then reduced with sodium bis(2-methoxyethoxy)aluminum hydride(70% in benzene) to give 1,3-diphenyl-3-azabicyclo[3.1.0]hexane.

EXAMPLE 18 Preparation of1-(p-Trifluoromethylphenyl)-3-azabicyclo[3.1.0]-hexane hydrochloride

Using the method of Example 6, ethyl p-(trifluoromethyl)phenyl acetateis converted to ethyl α-bromo-p-(trifluoromethyl)phenyl acetate [bp92°-95° C. (0.4 mm)] and this is reacted with ethyl acrylate-sodiumhydride to give diethyl1-(p-trifluoromethylphenyl)-1,2-cyclopropanedicarboxylate [bp 108°-110°C. (0.2 mm)]. Hydrolysis with 1 N potassium hydroxide givescis-1-(p-trifluoromethylphenyl)-1,2-cyclopropanedicarboxylic acid ascolorless crystals, mp 161°-162° C. This diacid is then reacted withurea to give 1-(p-trifluoromethylphenyl)-1,2-cyclopropanedicarboximideas colorless crystals, mp 164°-165° C.

To a solution of 3.5 g of this imide in 75 ml of benzene is added 20 mlof sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution).This is refluxed for one hour, cooled to room temperature and the excesshydride reagent is decomposed with 20 ml of 10 N sodium hydroxide. Thebenzene layer is washed with water, dried over magnesium sulfate andevaporated under reduced pressure to give an amber colored oil. This oilis dissolved in ether and dry hydrogen chloride gas is bubbled into thesolution. The resultant precipitate is collected by filtration andrecrystallized from isopropyl alcohol to give the product, mp 249°-251°C.

EXAMPLE 19 Preparation of3-(p-Chlorobenzyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane

A 19.35 g sample of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 gof sodium carbonate and 17.5 g of p-chlorobenzoyl chloride are reactedin benzene. The benzene is evaporated and the dark purple residue isdissolved in 200 ml of chloroform and washed successively with 5% sodiumcarbonate, 0.5 N hydrochloric acid and then with water and dried oversodium sulfate giving a dark purple oil. Addition of ether gives theproduct 3-p-chlorobenzoyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexaneas grey crystals, mp 98°-100° C.

A 16.60 g portion of3-(p-chlorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane(prepared above) is dissolved in 160 ml of benzene and 55.5 g of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) is addeddropwise. The mixture is refluxed for 2 hours, cooled and quenchedslowly with 10 N sodium hydroxide. Water is added, the organic layer isseparated and washed 3 times with water and then dried over sodiummagnesium sulfate. Removal of the solvent yields an off-white solid, mp88°-92° C.

In a like manner, reductions of the following amides with sodiumbis(2-methoxyethoxy)aluminum hydride yield the corresponding reducedproducts.

    ______________________________________                                        Amide             Reduction Product                                           ______________________________________                                        3-(2-naphthylcarbonyl)-                                                                         3-(2-naphthylmethyl)-                                       1-(p-chlorophenyl)-3-                                                                           1-(p-chlorophenyl)-3-                                       azabicyclo[3.1.0]hexane                                                                         azabicyclo[3.1.0]hexane                                     B                                                                             3-(5-norbornen-2-ylcar-                                                                         3-(5-norbornen-2-yl-                                        bonyl)-1-(p-chlorophenyl)-                                                                      methyl)-1-(p-chloro-                                        3-azabicyclo[3.1.0]hexane                                                                       phenyl)-3-azabicyclo-                                                         [3.1.0]hexane                                               C                                                                             3-acetyl-1-(p-amino-                                                                            3-ethyl-1-(p-amino-                                         phenyl)-3-azabicyclo-                                                                           phenyl)-3-azabicyclo-                                       [3.1.0]hexane     [3.1.0]hexane                                               D                                                                             1-(p-chlorophenyl)-3-                                                                           1-(p-chlorophenyl)-3-                                       propiolyl-3-azabicyclo-                                                                         propargyl-3-azabicyclo-                                     [3.1.0]hexane     [3.1.0]hexane                                               ______________________________________                                    

The above intermeidates A, B, and D are prepared by acylation of thecorresponding 3-azabicyclo[3.1.0]hexanes with the appropriate acidchloride, as described in Example 19.

The compound 3-acetyl-1-(p-aminophenyl)-3-azabicyclo[3.1.0]hexane isprepared by acetylation of 1-(p-nitrophenyl)-3-azabicyclo[3.1.0]hexane(Example 34), as in Example 19, followed by reduction with palladium oncharcoal in tetrahydrofuran.

EXAMPLE 20 Preparation of3-(1-Adamantylmethyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane

A sample of 19.35 g of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59g of sodium carbonate and 19.87 g of 1-adamantanecarboxylic acidchloride are reacted in accordance with Example 36, yielding the product3-(1-adamantylcarbonyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane asa white solid, mp 163°-165° C.

A 17.77 g portion of3-(1-adamantylcarbonyl)-1-(p-chlorophenyl-3-azabicyclo[3.1.0]hexane,(prepared above) is treated as described in Example 19 yielding a yellowoil which crystallizes to a white solid on standing, mp 72°-75° C.

EXAMPLE 21 Preparation of 3-Allyl-1-phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

To 18.7 g of 1-phenyl-1,2-cyclopropanedicarboximide in 100 ml ofdimethylformamide is added 5 g of sodium hydride (50% in mineral oil).The mixture is warmed on a steam bath and 9 ml of allyl bromide is addedover 5 minutes with stirring. This mixture is heated on a steam bath for1/2 hour, then at room temperature for 2 hours, poured into one liter ofwater and extracted with methylene chloride. The organic layer is mixedwith 50 g of magnesium silicate and evaporated on a rotary evaporator.This mixture is then added to 200 g of magnesium silicate in a Buchnerfunnel and eluted with one liter of petroleum ether and then one literof chloroform. The chloroform fraction is evaporated under reducedpressure giving N-allyl-1-phenyl-1,2-cyclopropanedicarboximide as acolorless oil.

To a solution of 8.0 g of the above product in 70 ml of benzene is added17.5 ml of sodium bis(2-methoxyethoxy)-aluminum hydride (70% benzenesolution). The mixture is refluxed for 2 hours and then stirred at roomtemperature for two hours. Processing as described in Example 19 yieldsthe desired product, mp 124°-128° C.

In a like manner, 1-(p-tolyl)-1,2-cyclopropanedicarboximide (Example 36)is reacted with allyl bromide to giveN-allyl-1-(p-tolyl)-1,2-cyclopropanedicarboximide which is then reducedas above to give 3-allyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride as colorless crystals, m.p. 165°-167° C.

In a like manner, 1-(p-tolyl)-1,2-cyclopropanedicarboximide (Example 36)is reacted with propargyl bromide to giveN-propargyl-1-(p-tolyl)-1,2-azacyclopropanedicarboximide which is thenreduced as above to give3-propargyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride.

EXAMPLE 22 Preparation of 3-Ethyl-1-phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

To 15.9 g of 1-phenyl-3-azabicyclo[3.1.0]hexane in 20 ml of pyridine isadded 20 ml of acetic anhydride. The mixture is allowed to standovernight at room temperature and then evaporated to give an oil. Thisoil is dissolved in a mixture of ether and methylene chloride, washedwith dilute hydrochloric acid and then sodium bicarbonate and dried overmagnesium sulfate and evaporated to a pale amber liquid. This liquid iscrystallized from hexane ot give the product3-acetyl-1-phenyl-3-azabicyclo[3.1.0]hexane mp 63°-65° C.

A 10.0 g portion of 3-acetyl-1-phenyl-3-azabicyclo[3.1.0]hexane,prepared above, in 100 ml of benzene is treated with 25 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) as describedin Example 19, yielding tan crystals, mp 148°-152° C.

EXAMPLE 23 Preparation of3-(Cyclohexylmethyl)-1-phenylazabicyclo[3.1.0]-hexane hydrochloride

A 6.4 g portion of 1-phenyl-3-azabicyclo[3.1.0]hexane is added to 60 mlof benzene. A 4.2 g portion of sodium carbonate in 40 ml of water isadded with stirring. A 5.9 g portion of cyclohexylcarbonyl chloride in40 ml of benzene is added and the mixture is stirred overnight. The oilysolid in the aqueous layer is extracted with chloroform. The extractsare washed with water and dilute hydrochloric acid, dried over magnesiumsulfate, filtered and evaporated. The oily residue is extracted withether giving a white solid as the product3-cyclohexylcarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexane, mp 81°-82° C.

A 7.0 g portion of3-cyclohexylcarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexane, prepared abovein 50 ml of benzene is treated with 13 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) and 13 ml of10 N sodium hydroxide, as described in Example 19, yielding thehydrochloride as colorless crystals, mp 215°-218° C.

EXAMPLE 24 Preparation of 1-(p-Methoxyphenyl)-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of 2.6 g of diethyl1-(p-methoxyphenyl)-1,2-cyclopropanedicarboxylate (prepared by themethod of Example 6 from ethyl-p-methoxyphenylacetate), 20 ml of 1 Npotassium hydroxide and 20 ml of ethanol is refluxed 3.5 hours and theethanol is removed by concentrating. A 20 ml portion of 1 N hydrochloricacid is added and then incremental portions of acid are added until thepH is one. The mixture is extracted three times with chloroform, driedand concentrated to a yellow solid. This solid is recrystallized fromethyl acetate-hexane to givecis-1-(p-methoxyphenyl)-1,2-cyclopropanedicarboxylic acid as a paleyellow solid.

A 6.6 g portion of this diacid, 2.4 g of urea and 300 ml of xylene isrefluxed and stirred for 24 hours. The mixture is cooled, diluted with25 ml of benzene, washed with water, dried, concentrated under reducedpressure to give a solid which is recrystallized from ethylacetate-hexane to give1-(p-methoxyphenyl)-1,2-cyclopropanedicarboximide.

A 3.0 g portion of the above product is mixed with 70 ml of benzene and20 ml of sodium bis(2-methoxyethoxy)-aluminum hydride (70% benzenesolution) is added over a 5 minute period with stirring. After stirringfor 1/2 hour and refluxing for one hour the mixture is cooled and 20 mlof 10 N sodium hydroxide is added followed by saturated sodium chloride.The organic layer is dried over magnesium sulfate, filtered andevaporated to an oil. The oil is dissolved in ether and hydrogenchloride gas is bubbled in. The solid which forms is recrystallized fromisopropyl alcohol giving pale pink plates, mp 174°-175° C.

EXAMPLE 25 Preparation of (+)-1-Phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

To a stirred slurry of 10 g of(+)-1-phenyl-1,2-cyclopropanedicarboximide in 300 ml of benzene undernitrogen is added 80 ml of sodium bis(2-methoxyethoxy)aluminum hydride(70% benzene solution). The mixture is stirred at room temperature for 2hours, refluxed for 4 hours, stirred at room temperature for 20 hoursand then 80 ml of 10 N sodium hydroxide is added slowly with stirring.The organic layer is washed with saturated sodium chloride, water, driedover magnesium sulfate and filtered. The filtrate is evaporated, etheris added and dry hydrogen chloride gas is bubbled in. The product isrecovered by filtration and recrystallized from acetonitrile givingcolorless needles, mp 169°-171° C., [α]_(D) ^(CH).sbsp.3^(0H) =+68° C.

EXAMPLE 26 Preparation of1-(p-Chlorophenyl)-3-(o-fluorobenzyl)-3-azabicyclo[3.1.0]hexanehydrochloride

A sample of 19.53 g of 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane,10.59 g of sodium carbonate and 15.8 g of o-fluorobenzoyl chloride arereacted to give the product3-(o-fluorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as abrown gum.

A 13.9 g portion of3-(o-fluorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane isreacted as described in Example 19 with 50 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) yielding alight yellow oil. This base is treated with ethanolic hydrochloric acidand ether to give the hydrochloride as a white solid, mp 204°-206° C.

In a similar manner,3-(p-fluorobenzoyl)-1-phenyl-3-azabicyclo[3.1.0]hexane is reduced bysodium bis(2-methoxyethoxy)aluminum hydride to give3-(p-fluorobenzyl)-1-phenyl-3-azabicyclo[3.1.0]hexane.

Likewise, 3-(m-fluorobenzoyl)-1-phenyl-3-azabicyclo[3.1.0]hexane isconverted to 3-(m-fluorobenzyl)-1-phenyl-3-azabicyclo[3.1.0]hexane.

EXAMPLE 27 Preparation of1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane

A solution of 59.5 g of 3,4-dichlorophenylacetic acid in 500 ml ofabsolute ethanol is saturated with anhydrous hydrogen chloride and thenheated at reflux for 2 hours. The mixture is concentrated under reducedpressure to 200 ml, diluted with 200 ml of water and neutralized withconcentrated ammonium hydroxide. This aqueous mixture is extracted 3times with chloroform. Concentration and decolorization of thechloroform extracts gives ethyl 3,4-dichlorophenylacetate as a yellowoil.

In a three-necked flask fitted with a Nichrome stirrer and a refluxcondenser is placed 7.0 g of ethyl 3,4-dichlorophenylacetate, 5.9 g ofN-bromosuccinimide, 0.1 g of benzoyl peroxide and 150 ml of carbontetrachloride. The reaction mixture is heated at reflux for 18 hours,cooled and filtered. The carbon tetrachloride filtrate is concentratedunder reduced pressure to give a deep orange liquid. Vacuum distillationat 115°-120° C. (0.5 mm) gives ethyl α-bromo-3,4-dichlorophenylacetateas a pale yellow liquid.

This product is converted to diethylcis-1-(3,4-dichlorophenyl)-1,2-cyclopropanedicarboxylate by the methodof L. L. McCoy, J. A. C. S., 80, 6568 (1958).

A mixture of 150 g of this diester and 66 g of 85% KOH in 500 ml ofwater and 500 ml of ethanol is refluxed for 6 hours and then chilled inice. The oily material is extracted into ether and the aqueous layer ismade acidic with 100 ml of 12 N hydrochloric acid. The oily lower layercrystallizes slowly to give a colorless crystalline cake. This isrecrystallized from a mixture of ethanol and ethyl acetate to givecolorless crystals of1-(3,4-dichlorophenyl)-1,2-cyclopropanedicarboxylic acid.

A mixture of 30.3 g of this diacid and 12.6 g of urea in one liter ofxylene is refluxed for 6 hours. The solvent is stripped under reducedpressure and the crystalline residue is slurried with water. Thecolorless crystals are collected by filtration, washed with water andair dried to give 1-(3,4-dichlorophenyl)-1,2-cyclopropanedicarboximide.

To 40 ml of 1 molar borane-tetrahydrofuran is added with stirring undernitrogen at 0° C. a solution of 2.56 g of this imide in 50 ml oftetrahydrofuran during 15 minutes. The solution is warmed in a steambath for 1 hour and is then cooled in ice, and then 20 ml of 6 Nhydrochloric acid is added, and the tetrahydrofuran is removed underreduced pressure. The residue is made basic with 75 ml of 5 N sodiumhydroxide and this is extracted with ether. The extract is dried overmagnesium sulfate, filtered, and the filtrate is saturated with hydrogenchloride. The precipitated crystals are collected by filtration and arerecrystallized from isopropyl alcohol to give 1.70 g of1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride ascolorless crystals, m.p. 180°-181° C.

The following imides, prepared in the above manner, are likewise reducedto the corresponding 3-azabicyclo[3.1.0]hexanes:

    ______________________________________                                        Imide             Reduction Product                                           ______________________________________                                        1-(p-ethylphenyl)-1,2-cyclo-                                                                    1-(p-ethylphenyl)-3-azabi-                                  propanedicarboximide, m.p.                                                                      cyclo[3.1.0]hexane hydro-                                   102°-104° C.                                                                      chloride, m.p. 207°-209° C.                   1-(p-hexylphenyl)-1,2-cyclo-                                                                    1-(p-hexylphenyl)-3-azabi-                                  propanedicarboximide, m.p.                                                                      cyclo[3.1.0]hexane hydro-                                   115°-117° C.                                                                      chloride, m.p. 181°-183° C.                   1-(m-tolyl)-1,2-cyclopropane-                                                                   1-(m-tolyl)-3-azabicyclo-                                   dicarboximide, m.p. 164°-                                                                [3.1.0]hexane hydrochloride,                                166° C.    m.p. 129°-131° C.                             1-(p-bromophenyl)-1,2-cyclo-                                                                    1-(p-bromophenyl)-3-azabi-                                  propanedicarboximide, m.p.                                                                      cyclo[3.1.0]hexane hydro-                                   150°-151° C.                                                                      chloride, m.p. 231°-233° C.                   1-(p-fluorophenyl)-1,2-cyclo-                                                                   1-(p-fluorophenyl)-3-azabi-                                 propanedicarboximide, m.p.                                                                      cyclo[3.1.0]hexane hydro-                                   146°-148° C.                                                                      chloride, m.p. 170°-172° C.                   ______________________________________                                    

In the above manner,N-benzoyl-1-(p-bromophenyl)-1,2-cyclopropanedicarboximide, made byreaction of 1-(p-bromophenyl)-1,2-cyclopropanedicarboximide with benzylchloride, as in Example 14, is converted to3-benzyl-1-(p-bromophenyl)-3-azabicyclo[3.1.0]hexane, m.p. 69°-70° C.

EXAMPLE 28 Preparation of1-(m-Methoxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride

A 92.3 g portion of m-anisidine is dissolved in 225 ml of concentratedhydrochloric acid, 150 ml of water and 150 g of ice and cooled to 0° C.This mixture is diazotized carefully with vigorous stirring at 0°-5° C.with 52.5 g of sodium nitrite in 120 ml of water. This mixture is thenadded to 83.25 g of N-methylmaleimide in 225 ml of acetone at 0° C. ThepH is adjusted to 3.0 and 25.5 g of cuprous chloride dihydrate is addedin one portion followed by 200 ml of acetone, with stirring. Evaporationof the acetone and decantation of the aqueous layer leaves a blackresidue which is boiled with one liter of benzene, dried over magnesiumsulfate and filtered through a Buchner funnel containing 50 g ofactivated magnesium silicate. The residue is boiled with one liter ofbenzene and filtered through activated magnesium silicate. The darkfiltrate is evaporated under reduced pressure and then heated for 10minutes with 100 ml of 2,6-lutidine to insure dehydrochlorination. Thissolution is combined with 500 ml of water and 400 ml of pyridine andfiltered. The crystalline cake is pressed free of dark oil and thenboiled with 500 ml of 90% ethanol. This is cooled and filtered giving2-(m-methoxyphenyl)-N-methylmaleimide as orange crystals, m.p. 138°-146°C.

This product is converted to1-(m-methoxyphenyl)-N-methyl-1,2-cyclopropanedicarboximide by the methodof P. T. Izzo, J. Organic Chemistry, 28, 1713 (1963).

To a mixture of 3.0 g of this imide in 70 ml of benzene is added 20 mlof sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution)over a 5 minute period under nitrogen with stirring. The mixture isstirred for 30 minutes, refluxed for one hour, cooled and 20 ml of 10 Nsodium hydroxide and then saturated sodium chloride are added. Theorganic layer is dried over magnesium sulfate, filtered and evaporatedgiving crystals which are recrystallized from ether. Reaction withhydrogen chloride gas and recrystallization form isopropyl alcohol givesthe crystalline product1-(m-methoxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride, mp148°-150° C.

EXAMPLE 29 Preparation of(+)-1-Phenyl-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride

A mixture of 10 g of (+)-1-phenyl-1,2-cyclopropanedicarboximide, 2.67 gof sodium hydride (50% in mineral oil), 50 ml of dimethylformamide and 5ml of methyl iodide is reacted and poured into 500 ml of water. Thismixture is extracted with methylene chloride, washed with water, driedover magnesium sulfate, and evaporated. The residue is adsorbed onactivated magnesium silicate in a Buchner funnel and washed with 250 mlof benzene. The eluate is washed with 500 ml of methylene chloride andevaporated giving green crystals of(+)-1-phenyl-N-methyl-1,2-cyclopropanedicarboximide.

A 3.0 g portion of this imide in 70 ml of dry benzene is reacted with 20ml of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzenesolution). The mixture is stirred for 15 minutes at room temperature andthen on a steam bath for 15 minutes. After cooling the reaction mixtureis treated as described in Example 12 giving(+)-1-phenyl-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride ascrystals, mp 188°-190° C., [α]_(D) ^(CH).sbsp.3^(OH) =+72°.

EXAMPLE 30 Preparation of1-(4-Chloro-α,α,α-trifluoro-m-tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride

Using the method of Example 6,methyl(4-chloro-α,α,α-trifluoro-m-tolyl)acetate is converted to methylbromo(4-chloro-α,α,α-trifluoro-m-tolyl)acetate, and this is reacted withmethyl acrylate-sodium hydride to give dimethyl1-(4-chloro-α,α,α-trifluoro-m-tolyl)cyclopropanedicarboxylate.Hydrolysis with 1 N potassium hydroxide givescis-1-(4-chloro-α,α,α-trifluoro-m-tolyl)-1,2-cyclopropanedicarboxylicacid as colorless crystals, mp 167°-169° C., and the diacid is thenreacted with urea to give1-(4-chloro-α,α,α-trifluoro-m-tolyl)-1,2-cyclopropanedicarboximide ascolorless crystals, mp 123°-124° C.

To a solution of 0.28 g of1-(4-chloro-α,α,α-trifluoro-m-tolyl)cyclopropanedicarboximide in 10 mlof benzene is added 1.0 ml of sodium bis(2-methoxyethoxy)aluminumhydride (70% benzene solution). This is refluxed for one hour, cooled toambient temperature, and the excess hydride reagent is decomposed withone ml of 10 N sodium hydroxide. The benzene layer is washed with water,dried over magnesium sulfate and evaporated under reduced pressure togive an amber-colored oil. This is dissolved in ether and dry hydrogenchloride is bubbled into the solution. The resultant precipitate iscollected by filtration and recrystallized from isopropyl alcohol togive 1-(4-chloro-α,α,α-trifluoro-m-tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride. Purification of the hydrochloride by recrystallizationfrom acetonitrile gives colorless crystals, m.p. 164°-166° C.

EXAMPLE 31 Preparation of3,6-Dimethyl-1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride

To a stirred solution of N, 3-dimethylcyclopropane-1,2-dicarboximide(U.S. Pat. No. 3,166,571, Ex. 2) in benzene is added sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) for severalminutes. This solution is stirred at ambient temperature for severalhours, refluxed for one hour, and then cooled and combined with sodiumhydroxide and worked-up and converted to the hydrochloride as describedin Example 11 to give the title product.

EXAMPLE 32 Preparation of1-(p-Acetamidophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane

To a suspension of 3-ethyl-1-(p-aminophenyl)-3-azabicyclo[3.1.0]hexane(Example 19) in aqueous sodium acetate is added acetic anhydride. Thisis heated on a steam bath for several minutes and filtered to give theproduct.

EXAMPLE 33 Preparation of1-(m-Hydroxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane

A solution of 1-(m-methoxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane in48% hydrobromic acid is refluxed for several hours and the solution ismade basic with sodium bicarbonate. The desired phenol is collected byfiltration.

EXAMPLE 34 Preparation of 1-(p-Nitrophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride

To a stirred slurry of 20.6 g of 1-phenylcyclopropane-1,2-dicarboxylicacid in 25 ml of concentrated sulfuric acid at 0° C. is added 15 ml ofconcentrated nitric acid over 30 minutes. The resultant solution is thenstirred at ambient temperature for 30 minutes and then poured onto ice.The crystalline product is recrystallized from hexane-ethyl acetate togive 1-(p-nitriphenyl)-cyclopropane-1,2-dicarboxylic acid as colorlesscrystals, m.p. 138°-144° C.

The above diacid is converted to1-(p-nitrophenyl)-1,2-cyclopropane-dicarboximide, m.p. 171°-173° C., bythe method described in Example 6.

A solution of the above imide in tetrahydrofuran is added to a 1 Msolution of borane-tetrahydrofuran at 0° C., under nitrogen. Thesolution is refluxed for one hour, cooled to 0° C. and then 6 Nhydrochloric acid is added. Tetrahydrofuran is removed under reducedpressure and the residual material is distributed between ether andsodium hydroxide. The ether solution, containing1-(p-nitrophenyl)-3-azabicyclo[3.1.0]hexane, is dried over magnesiumsulfate and filtered, and to the filtrate is added hydrogen chloride togive the product as a brown solid, m.p. 215°-217° C.

EXAMPLE 35 Preparation of 1-(o-Chlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride

A stirred mixture of 36.9 g of methyl o-chlorophenylacetate, 36.0 g ofN-bromosuccinimide, and 2 drops of 48% hydrobromic acid in 500 ml ofcarbon tetrachloride is refluxed for 20 hours and then filtered throughmagnesium silicate. Evaporation under reduced pressure gives methylα-bromo-o-chlorophenylacetate as a straw-colored liquid.

To a stirred suspension of 4.8 g of sodium hydride (50% in mineral oil)in 100 ml of benzene-N,N-dimethylformamide (1:1) is added a mixture of26.3 g of the above bromoester and 8.69 g of methyl acrylate over 1/2hour. The mixture is stirred at ambient temperature for 4 hours, excesssodium hydride is then decomposed with 2 ml of methanol, and thismixture is poured into 500 ml of water. The organic layer is washed withwater, dried over magnesium sulfate, and evaporated to givedimethyl-1-(o-chlorophenyl)-1,2-cyclopropanedicarboxylate as a brownoil.

The above diester (17.35 g) and 200 ml of 1 N potassium hydroxide in 50ml of ethanol is refluxed for 6 hours. The solution is reduced toone-half volume under reduced pressure and acidified to give1-(o-chlorophenyl)-1,2-cyclopropanedicarboxylic acid as a brown oil.

A mixture of 10.0 g of the above diacid and 3.4 g of urea in 500 ml ofxylene is refluxed for 6 hours. The solution is washed with water andsodium bicarbonate and then dried over magnesium sulfate to give a tansolid. Recrystallization from ethanol gives1-(o-chlorophenyl)-1,2-cyclopropanedicarboximide as colorless crystals,mp 154°-156° C.

To 1.35 g of the above imide in 30 ml of benzene is added 9 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (70% benzene solution) over 2minutes with stirring. The solution is stirred at ambient temperaturefor 15 minutes and is then refluxed for 30 minutes. To the cooledsolution is added 10 ml of 10 N sodium hydroxide and the benzene layeris washed with water, dried over magnesium sulfate and filtered. Thefiltrate is evaporated under reduced pressure and the residual oil isdissolved in ether and to this solution is added anhydrous hydrogenchloride gas. The precipitated product is recrystallized from isopropylalcohol to give 1-(o-chlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride as colorless crystals, mp 188°-190° C.

EXAMPLE 36 Preparation of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride

To 120 g of p-tolylacetic acid is added 230 ml of thionyl chloride andthe solution is allowed to stand at room temperature for 2 hours, afterwhich it is warmed to 60° C. for 1 hour. To this solution is added 285 gof N-bromosuccinimide and 10 drops of 48% hydrobromic acid and themixture is then refluxed on a 90° C. oil bath for 1 hour. An additional90 ml of thionyl chloride is added and refluxing continued for 45minutes. The mixture is distilled under reduced pressure to remove 250ml of thionyl chloride, and the residual liquid is poured into 500 ml ofcold methanol with stirring and ice cooling over 15 minutes. Thissolution is evaporated under reduced pressure to give a dark oil whichis dissolved in 100 ml of chloroform. The solution is washed with 500 mlof water, dried over magnesium sulfate and filtered. The filtrate isevaporated under reduced pressure to give a dark oil which is distilledto give 94 g of bromoester as a pale yellow liquid, bp. 115°-120° C.(0.05 mm). The pale yellow liquid is then reacted with methylacrylate-sodium hydride in ether (as in Example 6) to give dimethylcis-1-(p-tolyl)-1,2-cyclopropanedicarboxylate, mp 58°-59° C. Hydrolysiswith 1 N potassium hydroxide, followed by acidification withhydrochloric acid (as in Example 6), givescis-1-(p-tolyl)-1,2-cyclopropanedicarboxylic acid as colorless crystals,mp 188°-190° C. This diacid is then reacted with urea (as in Example 6)to give 1-(p-tolyl)-1,2-cyclopropanedicarboximide as pale yellowcrystals, mp 82°-85° C.

To a mixture of 20.1 g of this imide in 600 ml of benzene is added 160ml of sodium bis(2-methoxyethoxy)aluminum hydride and the reaction isrun as in Example 8 and then the excess reagent is decomposed with 160ml of 10 N sodium hydroxide. The benzene layer is washed with water,dried over magnesium sulfate and filtered. The filtrate is evaporatedunder reduced pressure to give a dark oil which is dissolved in ether,and then dry hydrogen chloride is bubbled into the solution. Theresultant precipitate is collected by filtration and recrystallized fromacetonitrile-methanol to give 12.1 g of1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as pale tan plates,mp 207°-208° C.

In the same manner as described in the above example,1-(p-cumyl)-1,2-cyclopropanedicarboximide, m.p. 147°-148° C. gives1-(p-cumyl)-3-azabicyclo[3.1.0]hexane hydrochloride, m.p. 231°-232° C.

The following imides are reduced in the above manner to give thecorresponding amine hydrochloride:

    ______________________________________                                        Imide             3-Azabicyclo[3.1.0]hexane                                   ______________________________________                                        1-(α,α,α-trifluoro-m-tolyl)-                                                  1-(α,α,α-trifluoro-m-tolyl)-              1,2-cyclopropanedicarbox-                                                                       3-azabicyclo[3.1.0]hexane                                   imide, m.p. 94°-95.5° C.                                                          hydrochloride, m.p. 146°-148° C.              1-(3-bromo-4-methoxyphenyl)-                                                                    1-(3-bromo-4-methoxyphenyl)-                                1,2-azacyclopropanedicar-                                                                       3-azabicyclo[3.1.0]hexane                                   boximide, m.p. 184°-186° C.                                                       hydrochloride, m.p. 108°-211° C.              1-(o-tolyl)-1,2-cyclopropane-                                                                   1-(o-tolyl)-3-azabicyclo[3.1.0]-                            dicarboximide     hexane hydrochloride                                        1-(p-cyclohexylphenyl)-1,2-                                                                     1-(p-cyclohexylphenyl)-3-azabi-                             cyclopropanedicarboximide                                                                       cyclo[3.1.0]hexane                                          1-(4-biphenyl)-1,2-cyclopro-                                                                    1-(4-biphenyl)-3-azabicyclo-                                panedicarboximide [3.1.0]hexane                                               ______________________________________                                    

EXAMPLE 37 Preparation of (+)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride

A solution of 94.8 g of racemic-1-(p-tolyl)-1,2-cyclopropanedicarboxylicacid (Example 36) and 73.8 g of (-)-α-(1-naphthyl)ethylamine in 300 mlof tetrahydrofuran is diluted with 300 ml of ethyl ether and is allowedto stand at room temperature until crystallization is complete. Themixture is filtered and the crystals which are collected are washed withcold tetrahydrofuran to give 4.95 g of a salt comprised of one molarequivalent of (+)-1-(p-tolyl)-1,2-cyclopropanedicarboxylic acid and onemolar equivalent of (-)-α-(1-naphthyl)ethylamine. The salt is shakenwith sodium hydroxide solution and ether. The aqueous phase is acidifiedwith 12 N hydrochloric acid and the product is collected by filtrationto give 26.0 g of (+)-1-(p-tolyl)-1,2-cyclopropanedicarboxylic acid ascolorless crystals, [α]_(D) ^(CH).sbsp.3^(OH) =+192°.

A 15.0 g portion of (+)-1-(p-tolyl)-1,2-cyclopropanedicarboxylic acid,6.6 g of urea and 500 ml of xylene is refluxed and stirred for 5 hours.The reaction mixture is then filtered hot and the filtrate is evaporatedunder reduced pressure to give(+)-1-(p-tolyl)-1,2-cyclopropanedicarboximide as colorless crystals,m.p. 148°-155° C.

A 14 g portion of the above product is mixed with 420 ml of benzene and112 ml of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzenesolution) is added over a 15 minute period with stirring. Afterrefluxing for 11/2 hours the mixture is cooled and 160 ml of 10 N sodiumhydroxide is added. The organic layer is dried over sodium sulfate,filtered and evaporated to an oil. The oil is dissolved in ether andhydrogen chloride gas is bubbled in. The solid which forms isrecrystallized from acetonitrile giving(+)-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorlesscrystals, m.p. 208°-210.5° C., [α]_(D) ^(CH).sbsp.3^(OH) =+64.5°.

The above racemic-diacid is combined with an equimolar amount of brucinein ethanol to give a salt comprised of one molar equivalent of(-)-1-(p-tolyl)-1,2-cyclopropanedicarboxylic acid and one molarequivalent of brucine, [α]_(D) ^(CH).sbsp.3^(OH) =-46°. Treatment ofthis salt, as above, gives (-)-1-(p-tolyl)-1,2-cyclopropanedicarboxylicacid as colorless crystals, [α]_(D) ^(CH).sbsp.3^(OH) =-189°.

In the above manner, (-)-1-(p-tolyl)-1,2-cyclopropanedicarboxylic acidis converted to (-)-1-(p-tolyl)-1,2-cyclopropanedicarboximide, m.p.145°-148° C., [α]_(D) ^(CH).sbsp.3^(OH) =-74°. and this is then reducedas above to give (-)-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochlorideas colorless crystals, m.p. 204°-207° C., [α]_(D) ^(CH).sbsp.3^(OH)=-64°.

EXAMPLE 38 Preparation of 3-Methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of 4.19 g of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride and 20 ml of water is made basic with sodium hydroxide,and this mixture is extracted with ether and the ether is evaporated togive an oil. This oil is combined with 40 ml of 97% formic acid and 35ml of 37% formaldehyde and the solution is heated on a steam bath for 2hours. The solution is cooled, made basic with sodium hydroxide andextracted with ether. The extract is dried over magnesium sulfate,filtered, and the filtrate is saturated with hydrogen chloride. Theprecipitated crystals are collected and recrystallized from isopropylalcohol to give 3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride ascolorless crystals, m.p. 197°-198° C.

The following amines can also be converted to the N-methyl derivative inthe above manner.

    ______________________________________                                        Amine               N-Methyl Derivative                                       ______________________________________                                        (+)-1-(p-tolyl)-3-azabicyclo-                                                                     (+)-3-methyl-1-(p-tolyl)-3-                               [3.1.0]hexane       azabicyclo[3.1.0]hexane                                   (-)-1-(p-tolyl)-3-azabicyclo-                                                                     (-)-3-methyl-1-(p-tolyl)-3-                               [3.1.0]hexane       azabicyclo[3.1.0]hexane                                   ______________________________________                                    

EXAMPLE 39 Preparation of 1-(p-Hydroxyphenyl)-3-azabicyclo[3.1.0]hexanehydrochloride

To a slurry of 7.2 g (0.15 mol) of sodium hydride (50% oil dispersion)in 170 ml of N,N-dimethylformamide at 0°-5° is added a solution of 10.1ml of ethanethiol in 85 ml of N,N-dimethylformamide over a 15 minuteperiod. An additional 3.16 g portion of sodium hydride is added followedby 14.4 g of 1-(p-methoxyphenyl)-3-azabicyclo[3.1.0]hexanehydrochloride. After the addition of 40 ml of N,N-dimethylformamide, themixture is refluxed for 4 hours and the solvent is then removed. Theresidue is dissolved in 150 ml of water and mineral oil is extractedwith ether. The aqueous solution is made acidic with acetic acid and theprecipitated crystals are collected by filtration to give 9.8 g of3-formyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane as tan crystals,m.p. 166°-167°.

A solution of 4.50 g of the above N-formyl derivative in 40 ml of 1.25 Nsodium hydroxide is heated on a steam bath for 3 hours under nitrogen.The chilled solution is neutralized with acetic acid and filtered togive 3.30 g of the amine as a tan powder, m.p. 174°-177°. This isdissolved in 20 ml of abs. ethanol and HCl gas is bubbled into thesolution. Evaporation of the liquid gives 3.78 g of(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride as tancrystals, m.p. 195°-196°.

EXAMPLE 40 Preparation of 1-(m-Hydroxyphenyl)-3-azabicyclo[3.1.0]hexanehydrochloride

In the manner of Example 39,1-(m-methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride is convertedto 3-formyl-1-(m-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane, m.p.129°-130° C. This is hydrolyzed with sodium hydroxide, as describedabove, to give 1-(m-hydroxyphenyl)-3-azabicyclo[3.1.0]hexanehydrochloride as pale tan crystals, m.p. 209°-210° C.

EXAMPLE 41 Preparation of 1-(p-Ethoxyphenyl)-3-azabicyclo[3.1.0]hexanehydrochloride

To a stirred mixture of 1.0 g of3-formyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane and 0.7 g ofpotassium carbonate in 25 ml of absolute ethanol is added a solution of3.2 g of ethyl iodide in 10 ml of absolute ethanol. The mixture isrefluxed for 2 hours and then is filtered and evaporated. The residualmixture of crystals and liquid is combined with water and this isextracted with chloroform and the extract is dried over magnesiumsulfate and evaporated to give 1.0 g of a colorless, viscous liquid,which crystallizes on standing. Recrystallization from hexane gives 0.31g of 3-formyl-1-(p-ethoxyphenyl)-3-azabicyclo[3.1.0]hexane as colorlesscrystals, m.p. 48°-51° C.

A solution of 2.0 g of this compound in 50 ml of ethanol and 20 ml of 5N sodium hydroxide is heated on a steam bath for 30 minutes and theethanol is then removed under reduced pressure. The residue is extractedwith ether and the extract is dried over magnesium sulfate, filtered,and then is evaporated to give1-(p-ethoxyphenyl)-3-azabicyclo[3.1.0]-hexane as colorless crystals,m.p. 48°-49° C. This is combined with ethanolic hydrogen chloride togive 1-(p-ethoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride ascolorless crystals, m.p. 192°-193° C.

EXAMPLE 42 Preparation of 1-Phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

A solution of 9.00 g of cis-1-phenyl-1,2-cyclopropanedicarboxylic acidin 100 ml of tetrahydrofuran is added to 180 ml of 1 Mborane-tetrahydrofuran at 0° C., under nitrogen over 15 minutes. Thesolution is kept at room temperature for 30 minutes and then is refluxedfor 4 hours. After cooling the reaction mixture in ice, 60 ml of 6 Nhydrochloric acid is added and the tetrahydrofuran is removed underreduced pressure. The aqueous residue is made basic with sodiumhydroxide and extracted with ether. The extract is dried over potassiumcarbonate and the filtered solution is evaporated to give 7.7 g ofcis-1-phenyl-1,2-cyclopropanedimethanol.

A solution of 6.00 g of the above diol in 335 ml of dichloromethane and14 ml of triethylamine is cooled to -10° C. and to this is added 8.45 gof methanesulfonyl chloride over 15 minutes. This is stirred at roomtemperature for 30 minutes and is then washed with cold dilutehydrochloric acid, then with cold water and finally with 10% sodiumbicarbonate solution. The organic solution is dried over magnesiumsulfate, and the filtered solution is evaporated to give 8.40 g of thedimethanesulfonate as a pale yellow oil. A solution of this oil in 100ml of tetrahydrofuran is combined with 1.0 g of sodamide and thismixture is refluxed with filtered. Evaporation of the solution gives1-phenyl-3-azabicyclo[3.1.0]hexane as a colorless liquid. Conversion ofthis amine to the hydrochloride with ethanolic hydrogen chloride gives1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride. When recrystallizedfrom acetonitrile, the product is obtained as colorless crystals, m.p.166°-167° C.

EXAMPLE 43 Preparation of1-(m-Chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride

By the method of Example 10,1-(m-chlorophenyl)-N-methyl-1,2-cyclopropanedicarboximide, m.p. 72°-73°C., prepared from 1-(m-chlorophenyl)-1,2-cyclopropanedicarboximide(Example 6) and methyl iodide gives1-(m-chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride ascolorless crystals, m.p. 180°-182° C.

EXAMPLE 44 Preparation of1-(p-Chlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane

Using the method of Example 19,1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane (Example 1) is reacted withacetyl chloride to give3-acetyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane and then isconverted to 1-(p-chlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane whichis obtained as a brown oil.

EXAMPLE 45 Preparation of3-[4,4-bis(p-Fluorophenyl)butyl]-1-phenyl-3-azabicyclo[3.1.0]hexaneFumarate

A mixture of sodium hydride and 1-phenyl-1,2-cyclopropanedicarboximide(U.S. Pat. No. 3,166,571) in dry N,N-dimethylformamide is stirred untilhydrogen evolution ceases. To this is added1-chloro-4,4-bis(4-fluorophenyl)butane and the mixture is stirred for 20hours at room temperature and then is heated briefly at 100° C. Themixture is combined with water and extracted with ether and the extractis evaporated to giveN-[4,4-bis(p-fluorophenyl)butyl]-1-phenyl-1,2-cyclopropanedicarboximideas a colorless glass.

Reduction of the above compound as in Example 10 and the combination ofthe base with fumaric acid gives3-[4,4-bis(p-fluorophenyl)butyl]-1-phenyl-3-azabicyclo[3.1.0]hexanefumarate as colorless crystals, m.p. 153°-155° C.

In the above manner 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide(U.S. Pat. No. 3,344,026) is converted toN-[4,4-bis(p-fluorophenyl)butyl]-1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide,m.p. 98°-99° C. This compound is reduced as in Example 27 and the baseis combined with fumaric acid to give3-[4,4-bis(p-fluorophenyl)butyl]-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexanefumarate as colorless crystals, m.p. 152°-154° C.

EXAMPLE 46 Preparation of3-[3-(p-Fluorobenzoyl)propyl]-1-phenyl-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of 15.9 g of 1-phenyl-3-azabicyclo[3.1.0]hexane (Example 9),20.1 g of γ-chloro-p-fluorobutyrophenone and 10 mg of potassium iodidein 100 ml of toluene is refluxed for 24 hours. Filtration gives 11.6 gof 1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride, m.p. 166°-167° C.Evaporation of the filtrate gives a brown oil which is combined with 2 Nhydrochloric acid and chloroform. The crystals which form in thechloroform layer are collected by filtration and recrystallized fromethanol to give 3.10 g of3-[3-(p-fluorobenzoyl)propyl]-1-phenyl-3-azabicyclo[3.1.0]hexanehydrochloride as pale tan crystals, m.p. 151°-153° C.

EXAMPLE 47 Preparation of 1-(m-Methoxyphenyl)-3-azabicyclo[3.1.0]hexanehydrochloride

Methyl-m-methoxymandelate is reacted with phosphorous tribromide by themethod of I. P. Beletskaya, Zh. Obshch. Khim., 34, 321 (1964) to givemethyl bromo-(m-methoxyphenyl)acetate as a pale yellow liquid, and usedbelow (without further purification).

In a like manner the following mandelate esters can be converted to thecorresponding bromoesters:

    ______________________________________                                        Mandelate ester  Bromoester                                                   ______________________________________                                        ethyl(p-hexyl)mandelate                                                                        ethyl bromo-(p-hexylphenyl)-                                                  acetate                                                      ethyl(p-isopropyl)mandelate                                                                    ethyl bromo-(p-cumyl)acetate                                 methyl(m-methyl)mandelate                                                                      methyl bromo-(m-tolyl)acetate                                methyl(o-methyl)mandelate                                                                      methyl bromo-(o-tolyl)acetate                                ______________________________________                                    

A mixture of 37.0 g of dimethyl1-(m-methoxyphenyl)-1,2-cyclopropanedicarboxylate (prepared by themethod of Example 6 from methyl bromo-(m-methoxyphenyl)acetate andmethyl acrylate), 20 g of potassium hydroxide and 200 ml of a 1:1water-methanol mixture is refluxed 16 hours and the methanol is removedby concentrating. Concentrated hydrochloric acid is added in incrementalportions until the pH is one. The mixture is extracted three times withether, dried and concentrated to givecis-1-(m-methoxyphenyl)-1,2-cyclopropanedicarboxylic acid as a paleyellow gum.

A 34.7 g portion of this diacid, 12 g of urea and 750 ml of xylene isrefluxed and stirred for 5 hours. The mixture is cooled, and thesupernatant solution is decanted and filtered through magnesiumsilicate, and the filtrate is concentrated under reduced pressure togive a solid which is recrystallized from ethanol to give1-(m-methoxyphenyl)-1,2-cyclopropanedicarboximide, m.p. 125°-127° C.

A 3.0 g portion of the above product is mixed with 75 ml of benzene and20 ml of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzenesolution) is added over a 5 minute period with stirring. After stirringfor 1/2 hour and refluxing for one hour the mixture is cooled and 20 mlof 10 N sodium hydroxide is added, followed by saturated sodiumchloride. The organic layer is washed with water and then is dried overmagnesium sulfate, filtered and evaporated to an oil. The oil isdissolved in ether and hydrogen chloride gas is bubbled in. The solidwhich forms is recrystallized from acetonitrile to give1-(m-methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorlesscrystals, m.p. 150°-152° C.

EXAMPLE 48 Preparation of1-(m-Hydroxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride

1-(m-Methoxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride iscombined with sodium hydride and ethanethiol in N,N-dimethylformamide asin Example 40 to give1-(m-hydroxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride.

EXAMPLE 49 Preparation of1-[(p-Methoxymethyl)phenyl]-3-azabicyclo[3.1.0]hexane hydrochloride

A mixture of 2.48 g ofcis-dimethyl-1-(p-tolyl)-1,2-cyclopropanedicarboxylate (Example 36) and1.78 g of N-bromosuccinimide and 5 mg of azabisisobutyronitrile in 50 mlof carbon tetrachloride is irradiated with a 500 watt tungsten lamp for2 hours. Filtration and evaporation of the filtrate givescis-dimethyl-1-(α-bromo-p-tolyl)-1,2-cyclopropanedicarboxylate as tancrystals which is used in the subsequent transformation without furtherpurification.

The above benzylic bromide is stirred with a methanolic solution ofsodium methoxide for 2 hours and then is refluxed for 3 hours and thenthe methanol is evaporated. The residue is partitioned between water anddichloromethane and the organic solution is evaporated to givecis-dimethyl-1-[(p-methoxymethyl)phenyl]-1,2-cyclopropanedicarboxylateas a dark oil which is used in the subsequent preparation withoutfurther purification.

The preceeding diester is hydrolyzed with ethanolic potassium hydroxideas in Example 6 to givecis-1-[(p-methoxymethyl)phenyl]-1,2-cyclopropanedicarboxylic acid as abrown oil.

The preceeding dicarboxylic acid is refluxed with urea in xylene as inExample 6 to give1-[(p-methoxymethyl)phenyl]-1,2-cyclopropanedicarboximide as colorlesscrystals, m.p. 122°-124° C.

The preceeding imide is reduced with borane-tetrahydrofuran as inExample 27 to give 1-[(p-methoxymethyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride.

EXAMPLE 50 Preparation of3-(n-Hexyl)-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane

The reaction of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane (Example 36) withsodium borohydride and hexanoic acid, using the reductive alkylationprocedure described by G. W. Gribble, et al., Synthesis, 702 (1975),gives 3-(n-hexyl)-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride,m.p. 182°-184° C.

EXAMPLE 51 Preparation of 1-(p-Tolyl)-3-azabicyclo[3.1.0]hexan-2-one

To a slurry of 5.0 g of sodium hydride (50% mineral oil dispersion) in350 ml of ether, and 0.5 ml of methanol, is added a solution of 24.0 gof methyl bromo-p-tolylacetate, 8.0 g of acrylonitrile and 1.0 ml ofmethanol at 20°-28° C. over a one-half hour period. After stirring foran additional hour, 10 ml of methanol is added and the ether solution iswashed with water. The organic phase is dried over sodium sulfate andand the filtered solution is evaporated to give 5.5 g of yellowcrystals. Recrystallization from ethanol gives 3.50 g ofcis-2-cyano-1-methoxycarbonyl-1-(p-tolyl)cyclopropane as colorlesscrystals, m.p. 88°-91° C.

To a solution of 2.15 g of the cyanoester in 100 ml of drytetrahydrofuran at 0° C. is added 7.5 ml of 1 M borane-tetrahydrofuran.This solution is refluxed for thirty minutes and then is held at roomtemperature for 2 hours. To the cooled solution is added 10 ml of 6 Nhydrochloric acid, and this solution is warmed on a steam bath for 15minutes and then is evaporated. The residue is extracted withdichloromethane and evaporation of the solution gives1-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one as a colorless oil, i.r. 5.90microns.

EXAMPLE 52 Preparation of 2-Methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride

Using the method of M. Takeda, et al., Chem. Pharm. Bull., 24, 2312(1976), 1-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one is reacted withmethyllithium followed by sodium borohydride. Excess reagents aredecomposed with methanol, followed by 1 N hydrochloric acid, and then 1N sodium hydroxide and then evaporation of the solution gives a residuewhich is dissolved in ether. This solution is dried over sodium sulfateand filtered, and to the filtrate is added dry hydrogen chloride.Filtration of this suspension gives2-methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride.

EXAMPLE 53 Preparation of1-(p-Chlorophenyl)-4-ethyl-3-azabicyclo[3.1.0]hexane

To 4.43 g of 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 100 mlof ether is added 16.4 ml of 2 M ethylmagnesium bromide. The mixture isallowed to stand at room temperature for 18 hours and then is combinedwith water. The ether solution is dried over sodium sulfate andevaporated to give 4.05 g of a pink semisolid. Crystallization fromether hexane gives1-(p-chloropehnyl)-4-ethyl-4-hydroxy-3-azabicyclo[3.1.0]hexan-2-one ascolorless crystals, m.p. 154°-157° C.

Evaporation of the mother liquor of the above crystallization gives1-(p-chlorophenyl)-4-ethyl-4-hydroxy-3-azabicyclo[3.1.0]hexan-2-one ascolorless crystals, m.p. 117°-124° C.

Reduction of the hydroxylactams, m.p. 117°-124° C. and 154°-157° C.,with sodium borohydride in methanol gives the epimeric1-(p-chlorophenyl)-4-ethyl-3-azabicyclo[3.1.0]hexanes.

EXAMPLE 54 Preparation of 1-(p-Tolyl)-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of 3-(p-tolylyl)-3-pyrroline, methylene iodide, and powderedcopper in a molar ration of 1:2:4 is heated in benzene for about 50hours. Filtration and evaporation of the solution gives1-(p-tolyl)-3-azabicyclo[3.1.0]hexane.

We claim:
 1. An optically active compound of the formula: ##STR46## wherein the phenyl moiety is mono-substituted from the group consisting of C₁ -C₆ alkoxy, amino, acetamido and hydroxy; X is selected from the group consisting of hydrogen, straight chain C₁ -C₈ alkyl, and a moiety of the formula C_(n) H_(2n) R₁, wherein n is an integer from 1 to 3 and R₁ is selected from the group consisting of phenyl and p-fluorobenzoyl; the racemic mixture thereof; the mirror image thereof; and the non-toxic pharmaceutically acceptable salts thereof.
 2. An optically active compound according to claim 1, wherein X is selected from the group consisting of hydrogen and straight chain C₁ -C₈ alkyl.
 3. The compound according to claim 1, 1-(p-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
 4. The compound according to claim 1, 1-(m-Methoxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride.
 5. The compound according to claim 1, 1-(p-Hydroxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
 6. The compound according to claim 1, 1-(p-Ethoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
 7. The compound 3-[3-(p-Fluorobenzoyl)propyl]-1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride.
 8. The compound according to claim 1, 1-(m-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
 9. The compound according to claim 1, 1-(m-Hydroxyphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane.
 10. An optically active compound of the formula: ##STR47## wherein the phenyl moiety is mono-substituted from the group consisting of C₁ -C₆ alkoxy methyl, X is selected from the group consisting of hydrogen, straight chain C₁ -C₈ alkyl, and a moiety of the formula C_(n) H_(2n) R₁, wherein n is an integer from 1 to 3 and R₁ is selected from the group consisting of halophenyl and bis-halophenyl; the racemic mixture thereof; the mirror image thereof; and the non-toxic pharmaceutically acceptable salts thereof.
 11. An optically active compound according to claim 10, wherein X is selected from the group consisting of hydrogen and straight chain C₁ -C₈ alkyl.
 12. An optically active compound according to claim 11, wherein the phenyl moiety is para or meta substituted from the group consisting of C₁ -C₆ alkoxymethyl; and X is as previously defined.
 13. An optically active compound according to claim 12, wherein the phenyl moiety is para or meta substituted from the group consisting of methoxymethyl and ethoxymethyl; and X is as previously defined.
 14. An optically active compound according to claim 13, wherein the phenyl moiety is substituted as previously defined; and X is selected from the group consisting of hydrogen and methyl.
 15. The compound according to claim 10, 1-[(p-Methoxymethyl)phenyl]-3-azabicyclo[3.1.0]hexane hydrochloride.
 16. An optically active compound of the formula: ##STR48## wherein the phenyl moiety is mono-substituted from the group consisting of C₁ -C₆ alkoxy, amino, acetamido and hydroxy; X is selected from the group consisting of C₃ -C₆ cycloalkylmethyl, C₃ -C₆ alkenyl and C₃ -C₆ alkynyl; the racemic mixture thereof; the mirror image thereof; and the non-toxic pharmaceutically acceptable salts thereof.
 17. An optically active compound according to claim 16, wherein X is selected from the group consisting of cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, allyl, butenyl, dimethylallyl and propargyl.
 18. The compound according to claim 1, 3-alkyl-1-(m-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane.
 19. The compound according to claim 16, 3-cyclopropylmethyl-1-(m-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane.
 20. The compound 3-(n-hexyl)-(m-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane.
 21. The compound according to claim 16, 1-(m-hydroxyphenyl)-3-propargyl-3-azabicyclo[3.1.0]hexane.
 22. The compound 1-(m-hydroxyphenyl)-3-(n-pentyl)-3-azabicyclo[3.1.0]hexane.
 23. An optically active compound of the formula: ##STR49##
 24. An optically active compound according to claim 23, wherein X is selected from the group consisting of hydrogen and straight chain C₁ -C₈ alkyl; and R is as previously defined.
 25. The compound according to claim 23, 2,3-dimethyl-1 (m-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane.
 26. The compound according to claim 23, 3,4-dimethyl-1-(m-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane.
 27. The compound according to claim 23, 1-(m-hydroxyphenyl)-2-methyl-3-azabicyclo[3.1.0]hexane.
 28. The compound according to claim 23, 1-(m-hydroxyphenyl)-4-methyl-3-azabicyclo[3.1.0]hexane.
 29. The compound 1-(3-bromo-4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride. 